Download Body mass index predicts discontinuation due to ineffectiveness and

BJD
British Journal of Dermatology
M E D I C A L D E R MA T O L O GY
Body mass index predicts discontinuation due to
ineffectiveness and female sex predicts discontinuation due
to side-effects in patients with psoriasis treated with
adalimumab, etanercept or ustekinumab in daily practice: a
prospective, comparative, long-term drug-survival study
from the BioCAPTURE registry*
J. Zweegers,1 J.M.P.A. van den Reek,1 P.C.M. van de Kerkhof,1 M.E. Otero,1 A.L.A. Kuijpers,2 M.I.A. Koetsier,3
W.P. Arnold,4 M.A.M. Berends,5 L. Weppner-Parren,6 P.M. Ossenkoppele,7 M.D. Njoo,7 J.M. Mommers,8 P.P.M.
€mig,1 R.J.B. Driessen,1 W. Kievit9 and E.M.G.J. de Jong1,10
van Lu
1
Department of Dermatology and 9Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Medical Center, Nijmegen,
the Netherlands
2
Maxima Medisch Centrum, Eindhoven/Veldhoven, the Netherlands
3
Gelre Ziekenhuizen, Apeldoorn, the Netherlands
4
Ziekenhuis Gelderse Vallei, Ede, the Netherlands
5
Slingeland Ziekenhuis, Doetinchem, the Netherlands
6
Jeroen Bosch Ziekenhuis, Den Bosch, the Netherlands
7
Ziekenhuisgroep Twente, Almelo/Hengelo, the Netherlands
8
St Anna Ziekenhuis, Geldrop, the Netherlands
10
Radboud University, Nijmegen, the Netherlands
Linked Comment: Egeberg. Br J Dermatol 2016; 175:247–248
Summary
Correspondence
Jeffrey Zweegers.
E-mail: [email protected]
Accepted for publication
19 February 2016
Funding sources
This work was supported by the University Medical Centre St Radboud Foundation, which received
funding from Pfizer, Janssen and AbbVie for the
project. Pfizer, Janssen and AbbVie played no role
in the design and execution of this study or in
data collection, data management, data analysis,
interpretation of the data, manuscript preparation,
manuscript review or manuscript approval.
Conflicts of interest
See Appendix 1 below.
*Plain language summary available online
DOI 10.1111/bjd.14552
340
Background Predictors for successful treatment are important for personalized medicine. Predictors for drug survival of biologics in psoriasis have been assessed,
but not split for different biologics or for the reason of discontinuation.
Objectives To compare long-term drug survival between the outpatient biologics
adalimumab, etanercept and ustekinumab in patients with psoriasis, and to elucidate predictors for overall survival and drug discontinuation due to ineffectiveness and side-effects for each biologic separately.
Methods Ten years of data were extracted from the prospective, multicentre, longterm BioCAPTURE registry. Kaplan–Meier survival analyses and confounder-corrected multivariate Cox regression analysis for drug survival (MCR-DS) were performed to compare drug survival between biologics. To elucidate the predictors
for different reasons of discontinuation for each biologic, univariate Cox regression analyses and multivariate Cox regression analyses for predictors (MCR-P)
with backward selection were performed.
Results In total, 526 treatment episodes – 186 adalimumab, 238 etanercept and
102 ustekinumab – were included covering 1333 treatment years. MCR-DS
showed a significantly higher overall survival for ustekinumab compared with
adalimumab and etanercept. MCR-P showed that higher body mass index (BMI)
was a predictor for discontinuation due to ineffectiveness for etanercept and
ustekinumab and that female sex was a predictor for discontinuation due to sideeffects for adalimumab, etanercept and ustekinumab.
Conclusions Ustekinumab has the highest confounder-corrected long-term drug
survival in psoriasis treatment, compared with adalimumab and etanercept.
British Journal of Dermatology (2016) 175, pp340–347
© 2016 British Association of Dermatologists
Long-term drug survival of biologics in psoriasis, J. Zweegers et al. 341
Higher BMI is a predictor for discontinuation due to ineffectiveness in etanercept
and ustekinumab, and female sex is a consistent predictor for discontinuation
due to side-effects in all three outpatient biologics.
What’s already known about this topic?
•
•
•
Drug survival of biologics for psoriasis has been analysed, but few publications
used prospective multicentre daily-practice data.
These studies found that ustekinumab had the highest confounder-corrected overall
drug survival, but they did not split survival analysis for the different biologics or
for different reasons of discontinuation.
Different predictors for overall drug survival were found in prospective and retrospective studies.
What does this study add?
•
•
•
This study reports on a longer period of drug survival than previous studies.
Ustekinumab has a higher confounder-corrected drug survival and higher survival
for discontinuation due to ineffectiveness and side-effects than adalimumab and
etanercept.
Higher body mass index (BMI) predicts discontinuation due to ineffectiveness in
etanercept and ustekinumab, and female sex is a consistent predictor for discontinuation due to side-effects in all three biologics.
Adalimumab (ADA), etanercept (ETA) and ustekinumab
(USTE) have enriched the therapeutic armamentarium of dermatologists by increasing the number of drugs available for
outpatient psoriasis treatment.1 In order to optimize psoriasis
treatment strategies in clinical practice, several real-world
studies have assessed drug survival of individual biologics,2–8
compared drug survival between biologics9–18 or searched for
clinical characteristics that might predict the discontinuation
of biological agents.2–7,9,11,12 Drug survival is a comprehensive measure of effectiveness and safety and the preferences of
both the patient and physician, and reflects the probability a
patient will stay on the drug over time.19
Although drug survival is becoming an increasingly popular
outcome measure in biological treatment of psoriasis, still only
a limited number of daily-practice studies are available that
used prospective data from multiple centres to compare biological agents.9–12 Also, several different clinical characteristics
have been stated to predict treatment discontinuation in
prospective and retrospective studies, but were usually analysed only for treatment discontinuation in general (i.e. overall
drug survival) and for all included biologics instead of performing analysis for each biologic separately. This has the
potential of missing important predictors, as predictors for
discontinuation might differ between different reasons of discontinuation and between biologics.
Among predictors for drug discontinuation in general,
female sex is mentioned most often, especially in prospective
studies.2,3,9,11,12,15 Female sex has also been found to predict
overall survival of biological treatment in other inflammatory
diseases.20 Thus far, research into predictors for
© 2016 British Association of Dermatologists
discontinuation split for ineffectiveness and side-effects has
gained little attention. Moreover, the few studies that have
addressed this issue have not been conducted with the same
variables at the start, leading to a heterogeneity in the selection of candidate predictors.2,3
In the current study, drug survival of the three biologics
was assessed with the aim to elucidate predictors for the drug
survival of ADA, ETA and USTE both as a group and separately
per biologic for overall drug survival, and drug failure due to
ineffectiveness and side-effects. The study set out to elucidate
the predictors for these most commonly prescribed outpatient
biologics in a uniform way, by selecting the candidate predictors from a set of baseline variables that were similar for each
biological treatment, and to elucidate predictors for different
reasons of discontinuation for each biologic separately. This
approach might aid physicians in their treatment strategies
and increase awareness for those patients at risk of discontinuing that specific biological treatment.
Patients and methods
BioCAPTURE
BioCAPTURE (Continuous Assessment of Psoriasis Treatment
Use Registry with Biologics) is a registry with prospective
clinical practice data on biological treatment of plaque psoriasis.10,21 Data from all real-world consecutive patients starting
biological treatment from one academic and eight nonacademic centres were included. Patients participating in clinical
trials were excluded. BioCAPTURE was approved by the
British Journal of Dermatology (2016) 175, pp340–347
342 Long-term drug survival of biologics in psoriasis, J. Zweegers et al.
medical ethics committee and, although not mandatory,
informed consent was obtained from every patient. Patients
with psoriasis were treated according to the European and
Dutch guidelines,22,23 and treatment recommendations were
made by the treating physician.
Data extraction
Patient characteristics and reason for treatment discontinuation (ineffectiveness, side-effects or other) were extracted
from BioCAPTURE for all patients from the inception of the
registry (2005) until May 2015. Baseline variables that were
extracted were age at start of biologic; sex; weight; body
mass index (BMI) divided into six categories9 (underweight < 185, normal weight 185–2499, overweight
250–2999, obese I 300–3499, obese II 350–3999, obese
III > 40 kg m 2); positive family history of psoriasis; psoriatic arthritis; duration of psoriasis until start of biologic;
baseline PASI score; biological naivety; antitumour necrosis
factor (anti-TNF) naivety and the presence of at least one
comorbidity in the medical history (hepatitis B or C, chronic
kidney or liver disease, HIV or cancer, except for nonmelanoma skin cancer)2,24 that would have excluded the
patient from participating in trials of biologics. When a
patient had received different biologics over time, the first
treatment episode of each biologic was used for analysis. In
case the patient interrupted the biological treatment for
≤ 90 days, the treatment episode was considered to be continuous. Ninety days is a widely accepted maximum interruption period.9,10,15 All available long-term data were used for
drug-survival and predictor analyses.
Long-term drug-survival analysis
Drug survival was analysed using Kaplan–Meier estimates. An
event in the overall survival analysis was defined as any discontinuation of biological treatment. Additional analyses for
the events ‘side-effects’ and ‘ineffectiveness’ were also carried
out. Censoring was performed for patients still on biological
treatment at the moment of data lock, or patients who were
lost to follow-up or for reasons other than the reason of
interest.
For USTE the last date plus 8, 10 or 12 weeks, depending
on the dosing regimen of the patient, was chosen for the primary analyses. As USTE has a low frequency of administration
and the discontinuation date can influence drug survival, a
sensitivity analysis was performed with the last date of injection of ustekinumab as the discontinuation date. This conservative approach is described in Appendix S1 (see Supporting
Information).
Confounder correction for long-term drug survival
Baseline variables were compared between treatment groups
using one-way ANOVA in case of parametric distribution and
the Kruskal–Wallis test in case of nonparametric distribution.
British Journal of Dermatology (2016) 175, pp340–347
Categorical variables were compared using the v2-test. Significantly different characteristics between ADA, ETA and USTE
were corrected for with multivariate Cox regression analysis
for drug survival (MCR-DS) in order to adjust for their possible confounding effect when comparing drug survival
between different biologics. Some variables were highly correlated and therefore only one variable was chosen for the confounder correction based on P-value; weight was chosen over
BMI and biologic naivety was chosen over anti-TNF-a naivety.
Sex and age at the start of the biologic were set as fixed variables. Possible confounders, that is the variables that were significantly different between treatment groups, were added as
covariates to the MCR-DS. Hazard ratios were extracted from
the models and are described.
Predictors for drug survival
To elucidate the predictors for drug survival of ADA, ETA and
USTE as a group and separately per biologic for overall drug
survival, and drug failure due to ineffectiveness and sideeffects, firstly all baseline variables were tested with univariate
Cox regression analysis with the P-value set at < 02. Possible
predictor variables were then incorporated in the multivariate
Cox regression analysis for predictors (MCR-P, to distinguish
this multivariate analysis from the previously mentioned MCRDS). On the basis of the univariate analysis, BMI was chosen
over weight for the multivariate analyses with MCR-P. For
MCR-P, backward selection was performed to elucidate the
final predictors.
All analyses were performed with SPSS version 20.0 (IBM,
Armonk, NY, U.S.A.). A P-value < 005 was considered significant. Variables with a Gaussian distribution were presented as
mean SD, nonparametrically distributed variables as median
(interquartile range) and categorical data as n (%).
Results
Patients
In total, 526 treatment episodes were included – 186 ADA,
238 ETA and 102 USTE – with a total of 1333 years of treatment. The characteristics of the patients at inclusion in BioCAPTURE are shown in Table 1. The majority of patients were
male (609%, n = 226), overweight (median BMI 278) and
had a positive family history of psoriasis (660%). Psoriatic
arthritis was present in 286% of patients. The median PASI
score at baseline was 132.
Baseline patient characteristics
The baseline patient characteristics per biologic are presented
in Table 2. The median baseline weight was significantly
higher for USTE (920 kg) and ADA (880 kg) than for ETA
(840 kg; P = 0002 and 0025, respectively). The median
baseline BMI was significantly higher for ADA (290 kg m 2)
and USTE (282 kg m 2) than for ETA (277 kg m 2;
© 2016 British Association of Dermatologists
Long-term drug survival of biologics in psoriasis, J. Zweegers et al. 343
Table 1 Baseline patient characteristics
Baseline patient characteristics
Age at start of biologic (years),
mean SD
Sex (male), n (%)
Height (cm), mean SD
Weight (kg), median (IQR)
Body mass index (kg m 2),
median (IQR)
Positive family history of
psoriasis (yes), n (%)
Psoriatic arthritis diagnosed by
a rheumatologist (yes), n (%)
Duration of psoriasis until start
of biologic (years), median (IQR)
Baseline PASI score, median (IQR)
First ever treatment
episode in BioCAPTURE
(n = 371)
475 128
226 (609)
1754 89a
860 (220)b
278 (66)a
245 (660)c
106 (286)d
overall drug survival was in favour of USTE (1 year: 840%
USTE, 758% ETA, 746% ADA; 5 year: 61% USTE, 41% ADA
and 34% ETA). The percentages decreased for ADA to 35% at
6 years and for ETA to 20% at 10 years of treatment. Survival
rates of drug survival split for ineffectiveness were again in
favour of USTE with percentages of 79% for USTE, 54% for
ADA and 45% for ETA at 5 years of treatment. These percentages decreased further for ADA to 50% at 6 years and for ETA
to 31% at 10 years. Five-year survival percentages for discontinuation due to side-effects were 83% for USTE, 80% for ETA
and 76% for ADA. These percentages were 70% for ADA at
6 years and 70% for ETA at 10 years of treatment. Sensitivity
analyses yielded similar percentages (Appendix S1; see Supporting Information).
199 (176)e
132 (77)f
IQR, interquartile range; PASI, Psoriasis Area and Severity Index.
Missing data: a79, b75, c13, d18, e2, f11.
P = 0033 and P = 0029, respectively), but not for ADA
compared with USTE (P = 0094). The median baseline PASI
score was significantly higher for USTE (134) and ETA
(132) than for ADA (111; P = 0007 and P < 0001, respectively). Patients were significantly less often biologic naive and
anti-TNF-a naive in treatment episodes of USTE compared
with ADA (P = 0004 and P = 0012, respectively) and ETA
(P < 0001 in both analyses).
Long-term drug-survival analysis
All available data on long-term drug survival for ADA, ETA
and USTE are shown in Figure 1. During 5 years of treatment,
Comparing long-term drug survival corrected for
confounders
Confounder correction was performed on drug-survival analysis by incorporating the significantly different baseline patient
characteristics into MCR-DS (Table 2). Age and sex were set as
fixed variables. Using all long-term data (Fig. 1), overall drug
survival corrected for confounders showed a significantly
higher value for USTE compared with ADA [hazard ratio (HR)
174, 95% confidence interval (CI) 109–280] and for USTE
compared with ETA (HR 216, 95% CI 131–356). For ADA
and ETA, overall survival was similar (HR 077, 95% CI 056–
107).
Confounder-corrected drug survival of discontinuation due
to ineffectiveness showed a significantly higher survival for
USTE compared with ADA (HR 274, 95% CI 142–528) and
for USTE compared with ETA (HR 291, 95% CI 146–578).
Survival of ADA vs. ETA showed no differences (HR 080,
95% CI 054–117). Confounder-corrected drug survival of
discontinuation due to side-effects showed a significantly
Table 2 Baseline patient characteristics per biologic
Baseline patient characteristics
Adalimumab (n = 186)
Etanercept (n = 238)
Ustekinumab (n = 102)
Age at start of biologic (years),
mean SD
Sex (male), n (%)
Height (cm), mean SD
Weight (kg), median (IQR)
BMI (kg m 2), median (IQR)
Positive family history of
psoriasis (yes), n (%)
Psoriatic arthritis (yes), n (%)
Duration of psoriasis until start of
biologic (years), median (IQR)
Baseline PASI score, median (IQR)
Biologic naive (yes), n (%)
Anti-TNF-a naive (yes), n (%)
487 128
469 127
501 125
0072a
106 (570)
1755 85 (missing: 16)
880 (240) (missing: 16)
290 (65) (missing: 17)
127 (683) (missing: 6)
146 (613)
1748 85 (missing: 66)
840 (243) (missing: 65)
277 (35) (missing: 66)
154 (647) (missing: 6)
66 (647)
1767 89 (missing: 8)
920 (212) (missing: 4)
282 (67) (missing: 8)
69 (676) (missing: 3)
041b
022a
0005c
0038c
064b
61 (328) (missing: 7)
205 (184) (missing: 2)
71 (298) (missing: 5)
204 (105)
28 (275) (missing: 9)
196 (96)
033b
085c
111 (72) (missing: 7)
65 (349)
73 (392)
132 (82) (missing: 7)
152 (639)
174 (731)
134 (115) (missing: 4)
19 (186)
25 (245)
IQR, interquartile range; BMI, body mass index; PASI, Psoriasis Area and Severity Index; TNF, tumour necrosis factor. aOne-way
b 2
v -test, cKruskal–Wallis test.
© 2016 British Association of Dermatologists
P-value
< 0001c
< 0001b
< 0001b
ANOVA,
British Journal of Dermatology (2016) 175, pp340–347
344 Long-term drug survival of biologics in psoriasis, J. Zweegers et al.
(a)
(b)
(c)
Fig 1. (a) Ten-year drug survival for adalimumab, etanercept and ustekinumab. (b) Ten-year drug survival with discontinuation due to
ineffectiveness split per biologic. (c) Ten-year drug survival with discontinuation due to side-effects split per biologic.
higher survival of USTE compared with ADA (HR 235, 95%
CI 102–537) and USTE compared with ETA (HR 258, 95%
CI 102–652). Drug survival of ADA compared with ETA was
not statistically different (HR 093, 95% CI 052–166). Oneand 5-year confounder-corrected drug-survival data are presented in Appendix S1 (see Supporting Information).
Predictors for long-term drug survival
Variables from the univariate analyses that were incorporated
into MCR-P for the different biologics are shown in Table S1
(see Supporting Information).
Predictors for adalimumab, etanercept and ustekinumab
as one group of biologics
MCR-P for overall survival showed that female sex (HR 145,
95% CI 110–192) and higher BMI (HR 118, 95% CI 104–
134) were predictors of discontinuation. MCR-P showed that
higher BMI (HR 125, 95% CI 108–146) and biological
naivety (HR 139, 95% CI 100–193) were predictors of discontinuation due to ineffectiveness and that female sex (HR
283, 95% CI 179–472) was a predictor of discontinuation
due to side-effects.
Predictors for adalimumab
MCR-P for overall survival, as well as for survival due to ineffectiveness, yielded no significant predictors. BMI was the last
variable in both analyses, but was not significant. MCR-P for
side-effects showed that female sex (HR 291, 95% CI 135–
629) was a predictor of discontinuation.
Predictors for etanercept
Female sex (HR 177, 95% CI 118–264), higher BMI (HR
125, 95% CI 104–151) and the presence of specific comorbidities (HR 189, 95% CI 104–346) were predictors of
overall discontinuation. MCR-P showed that higher BMI (HR
134, 95% CI 107–168) was a predictor for discontinuation
British Journal of Dermatology (2016) 175, pp340–347
due to ineffectiveness. Female sex (HR 233, 95% CI 101–
535), higher BMI (HR 147, 95% CI 101–208) and age at
start of ETA treatment (HR 142, 95% CI 106–192) were
predictors for discontinuation due to side-effects.
Predictors for ustekinumab
MCR-P showed that higher BMI (HR 143, 95% CI 101–
203) was a predictor for overall survival. Higher BMI (HR
198, 95% CI 122–321) was a predictor for discontinuation
due to ineffectiveness, and female sex (HR 402, 95% CI
100–1613) was a predictor of discontinuation due to sideeffects. In the group of patients with bodyweight > 100 kg
who failed USTE due to ineffectiveness, five (83%) of six
patients were treated with 90 mg and were thus treated
according to the guidelines.22,23
The results of sensitivity analyses for drug survival of USTE
from the date of last injection are presented in Figures S1–S3
(see Supporting Information).
Side-effects resulting in discontinuation of the biological
agent in female and male patients
In total, 79 patients discontinued their biological treatment
due to side-effects: 30 (38%) for ADA, 40 (51%) for ETA and
nine (11%) for USTE. Side-effects per biologic are presented
in Table S2 (see Supporting Information). Forty-five (57%) of
the 79 patients were female. The numbers of female/male
patients with side-effects leading to treatment discontinuation
were 20 (25%)/10 (94%) for ADA, 19 (21%)/21 (14%) for
ETA and six (17%)/three (4%) for USTE. There was a heterogeneity in experienced side-effects, and no pattern in the type
of side-effect was found between female and male patients.
Infections, mainly of the respiratory tract, were a common
reason for discontinuing ADA and ETA, but not USTE treatment. There were also no patterns found for infections
between female and male patients, or between ADA and ETA.
The only side-effects that could be characterized as typical for
female patients were a cystitis in one female patient during
ADA treatment, breast cancer in one female patient on ETA
© 2016 British Association of Dermatologists
Long-term drug survival of biologics in psoriasis, J. Zweegers et al. 345
treatment and cervical cancer in one female patient on ETA
treatment. One female patient on ADA treatment and one male
patient on ETA treatment stopped their treatment due to feelings of depression.
Biological dose
The mean SD cumulative doses of the biologics were
2783 2353 mg for ADA, 9720 8746 mg for ETA and
632 587 mg for USTE (ADA, 50 18 mg per 2 weeks;
ETA, 76 18 mg per week; USTE ≤ 100 kg, 69 32 mg
per 12 weeks; USTE > 100 kg, 97 38 mg per 12 weeks).
In our cohort, patients treated with ADA and ETA more often
had a dose increase (i.e. a higher dose than the recommended
label dose) than patients treated with USTE (ADA 40%, ETA
69%, USTE 27% of patients).
Discussion
This prospective, comparative, multicentre, long-term drugsurvival study showed that a higher BMI was a predictor for
drug discontinuation due to ineffectiveness for ETA and USTE,
and that female sex was a consistent predictor for discontinuation due to side-effects for ADA, ETA and USTE. USTE had the
highest confounder-corrected long-term drug survival in psoriasis treatment, compared with ADA and ETA.
Consistently with our study, a higher BMI was previously
found to predict overall biological discontinuation in psoriasis
treatment.25–27 BMI was also a predictor of overall biological
survival in patients with rheumatoid arthritis.28 However,
overall biological survival is a result of drug discontinuation
due to ineffectiveness, side-effects and other reasons.19 Of
these, ineffectiveness is the main reason for discontinuation of
biologics in psoriasis treatment.9,11 Highlighting the predictors
for ineffectiveness is therefore of interest. Our study elucidated
that a higher BMI is a predictor of biological discontinuation
due to ineffectiveness for both ETA and USTE, but was not a
significant predictor for drug survival of ADA. Given the current results from different studies, one might consider that
patients with psoriasis with a higher BMI should be encouraged to lose weight before and during their biological treatment. Indeed, a recently performed randomized controlled
trial showed a positive effect of a diet–exercise combination
over an information-only strategy on psoriasis severity in
patients with psoriasis who were being treated with systemic
agents such as biologics.29 In another randomized trial, psoriasis severity was significantly lower in the diet group than in
the control group at 24 weeks of biological treatment.30
Previous studies on overall drug survival of biologics as a
group have stated that female sex was a predictor for biological discontinuation in psoriasis treatment.2,3,9,11,12,15 Also, in
rheumatoid arthritis and in axial spondyloarthritis, female sex
predicted overall drug discontinuation of anti-TNF-a therapies
grouped together.20,31 So far, only one study on predictors
has highlighted ADA treatment for psoriasis by using data
from a smaller BioCAPTURE cohort, and found that female
© 2016 British Association of Dermatologists
sex was a predictor for ADA discontinuation due to sideeffects.2 Our present study with extended data from BioCAPTURE shows that female sex is a predictor for drug discontinuation due to side-effects for ADA, ETA and USTE in psoriasis
treatment.
The exact reason behind this is unclear. No different pattern
in the type or severity of side-effects was found between female
and male patients in our study. The fact that female sex is a predictor in all three biologics suggests that there is no class effect
and that other reasons should be considered. For example,
although scarce, publications on this topic have demonstrated
sex differences in the presentation of symptoms, prognosis of
diseases and treatment outcomes, as well as in communication.32 In a study regarding hospital inpatients it was shown
that severe adverse drug reactions were seen more often in
women than in men.33 Regardless of the underlying reason,
our results can increase the awareness among physicians that
female patients have a higher chance of discontinuing biological therapy for psoriasis due to side-effects than male patients.
There are several studies that have assessed biomarkers in
order to predict treatment success for the individual patient,
such as genetic, blood or tissue biomarkers.34 However,
patient characteristics can also serve as predictors for treatment
success. Our analyses contribute to the first steps of developing a predictive model for biological treatment in psoriasis.
Other large prospective studies are needed to confirm our
results.
So far, only a small number of daily-practice studies have
used prospective data from multiple centres to compare biological agents.9–12 Similar to the findings in these studies, our
study with long-term data showed that USTE had the highest
confounder-corrected overall drug survival compared with
both ADA and ETA. Unique in our study is the confoundercorrected drug survival split for discontinuation due to ineffectiveness and side-effects. Again, USTE had the highest drug
survival in both analyses compared with ADA and ETA. Moreover, infliximab and not USTE was the last-resort biologic for
psoriasis treatment in this study. Also, doses were more often
higher than the label dose in the order ETA > ADA > USTE.
We do not expect that the missing data on weight had a
major influence on our presented confounder-corrected drugsurvival outcomes, as ETA had more cases in total than USTE.
Indeed, our results were similar when missing data on weight
were imputed by the median weight of patients for that biologic. Our data, together with data from previous studies,
might aid physicians in their choice of long-term biological
treatment for patients with psoriasis.
A limitation of our study is the lower number of patients
than in nationwide registries from larger countries.9 Strengths
of our study are the detailed documentation of patient characteristics in our registry, the multicentre and prospective setting, and the performed drug-survival analyses split for each
biologic and split for reasons of discontinuation. Furthermore,
candidate predictors were chosen from baseline variables that
were similar for all biologics, increasing the homogeneity in
analysis.
British Journal of Dermatology (2016) 175, pp340–347
346 Long-term drug survival of biologics in psoriasis, J. Zweegers et al.
In conclusion, this prospective, comparative, multicentre,
long-term drug-survival study shows that higher BMI is a predictor for drug discontinuation due to ineffectiveness for ETA
and USTE, and that female sex is a consistent predictor for discontinuation due to side-effects for ADA, ETA and USTE. Furthermore, USTE has the highest confounder-corrected longterm drug survival. Comparative results from the long-term
drug survival aid the physician in choosing the most suited
long-term treatment for their individual patients with psoriasis. Our data also help to increase the awareness among physicians that higher BMI influences drug survival in ETA and
USTE, and that female patients are prone to discontinue ADA,
ETA and USTE because of side-effects.
14
15
16
17
18
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Appendix 1
J.Z. carries out trials for AbbVie, Janssen and Sciderm; and has
received research grants for the independent research fund of
the Department of Dermatology of Radboud UMC Nijmegen,
the Netherlands from AbbVie. J.M.P.A.vdR. carries out clinical
trials for AbbVie and Janssen; has received speaking fees from
Eli Lilly and AbbVie; and has received research grants for the
independent research fund of the Department of Dermatology
of Radboud UMC Nijmegen, the Netherlands from AbbVie
and reimbursement for attending a symposium from Janssen,
Pfizer and AbbVie. P.C.M.vdK. serves as a consultant for Merck
Sharp Dohme, Celgene, Centocor, Almirall, UCB, Pfizer, Sofinnova, AbbVie, Actelion, Galderma, Novartis, Janssen-Cilag, Eli
Lilly, Amgen, Mitsubishi and LEO Pharma; and receives
research grants from Centocor, Pfizer, Merck Sharp Dohme,
Merck Serono, AbbVie and Philips Lighting. E.M.G.J.dJ. has
© 2016 British Association of Dermatologists
received research grants for the independent research fund of
the Department of Dermatology of Radboud UMC Nijmegen,
the Netherlands from Merck-Serono, Wyeth, AbbVie, Pfizer
and Janssen; and has acted as a consultant and/or paid speaker
for and/or participated in research sponsored by companies
that manufacture drugs used for the treatment of psoriasis,
including AbbVie, Janssen, MSD, Pfizer, Amgen and Lilly.
M.D.N. serves as a consultant for Janssen. J.M.M. served as a
consultant for Novartis and Celgene. W.P.A. served as a consultant for AbbVie and Janssen and travelled with Pfizer, AbbVie and Janssen to medical congresses for 50% of the fees.
Supporting Information
Additional Supporting Information may be found in the online
version of this article at the publisher’s website:
Appendix S1. Sensitivity and survival analyses.
Fig S1. Ten-year overall drug survival with ustekinumab
from the last date of injection.
Fig S2. Ten-year drug survival with discontinuation due to
ineffectiveness: sensitivity analysis with ustekinumab from the
last date of injection.
Fig S3. Ten-year drug survival with discontinuation due to
side-effects: sensitivity analysis with ustekinumab from the last
date of injection.
Table S1. Variables selected as possible predictors from univariate Cox regression analyses.
Table S2. Side-effects leading to discontinuation of the biologic reported per agent.
Audio S1. Author Audio
British Journal of Dermatology (2016) 175, pp340–347