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BJD

T H E R A P E U T I CS British Journal of Dermatology

Comparison of long-term drug survival and safety of


biologic agents in patients with psoriasis vulgaris*
R. Gniadecki,1 B. Bang,1 L.E. Bryld,2 L. Iversen,3 S. Lasthein4 and L. Skov5
1
Department of Dermatology, Bispebjerg Hospital, Bispebjerg, Denmark
2
Department of Dermatology Roskilde Hospital, University of Copenhagen, Copenhagen, Denmark
3
Department of Dermatology, Marselisborg Hospital, Aarhus University, Aarhus, Denmark
4
Department of Dermatology, Odense Hospital, University of Southern Denmark, Odense, Denmark
5
Department of Dermatology Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark

Summary

Correspondence Background Drug survival (time to drug discontinuation) has recently emerged as
Robert Gniadecki. an important parameter reflecting the long-term therapeutic performance in a
E-mail: r.gniadecki@gmail.com real-life setting. Biologic drug survival in psoriasis is mainly limited by a gradual
loss of efficacy over time. Previous studies have been limited by small patient
Accepted for publication
6 August 2014 population size and short observation times and yielded discrepant survival times
for different biologics.
Funding sources Objectives To calculate the long-term drug survival for adalimumab, etanercept,
No external funding. infliximab and ustekinumab in a large cohort of real-life patients with psoriasis
vulgaris and to analyse the factors that influence drug survival.
Conflicts of interest
Patients and methods Data were extracted from the prospective registry DERMBIO
R.G. reports carrying out clinical trials for Abbvie,
MSD, Celgene, Novartis, Janssen and Pfizer and
covering all patients with psoriasis vulgaris treated with biologic agents in the
has had paid consultancies and lectures from Abb- academic centres in Denmark. Drug survival was analysed using the KaplanMeier
vie, MSD, Janssen and Pfizer. B.B. has been a method. The influence of different covariates on drug survival was analysed by
member of the advisory boards and a consultant Cox regression.
for Abbvie, Biogen Idec, Janssen and MSD and an Results Included in the analysis were 1867 treatment series (adalimumab n = 774,
investigator in clinical trials for Eli Lilly and Pfiz-
etanercept n = 449, infliximab n = 253, ustekinumab n = 391) administered in
er; B.B. is currently employed by LEO Pharma.
L.E.B. has no conflicts of interests. L.I. has had
1277 patients for up to 10 years. Drug survival was significantly longer for us-
paid lectureships and consultancies for Abbvie, Al- tekinumab than for anti-tumour necrosis factor (TNF)-a agents (P < 0001). Eta-
mirall, Janssen, LEO Pharma, MSD, Novo Nor- nercept had the shortest survival time [median survival 30 months, 95%
disk, Otsuka, Pfizer and UCB Nordic and has confidence interval (CI) 251349] whereas adalimumab and infliximab had
performed clinical trials for Abbvie, Amgen, Cell- comparable survival rates (59 months, 95% CI 456724; 44 months, 95% CI
gene, MSD, Pfizer, Eli Lilly and Novartis. S.L. has
33549, respectively). Survival was longer in men [odds ratio (OR) 151, 95%
had paid consultancies from Abbvie and Galderma
Nordic. L.S. has served as investigator, advisory CI 131174 vs. women] and in patients who had not previously received any
board member and paid consultant for Abbvie, biologic agent (OR 124, 95% CI 105146). Loss of efficacy accounted for 67%
Amgen, Astellas, Biogen Idec, Eli Lilly, Janssen, of all drug discontinuations.
LEO Pharma, MSD, Novartis and Pfizer. The Conclusions Ustekinumab has a significantly longer drug survival than the anti-
authors do not have equity in pharmaceutical
TNF-a agents. Switching from one biologic to another is associated with an
companies.
impairment of drug survival. Preventing loss of efficacy is a major area of medi-
*Plain language summary available online. cal need in the biologic therapy of psoriasis and the strategies that improve drug
survival should be further investigated.
DOI 10.1111/bjd.13343

Whats already known about this topic?


Gradual loss of efficacy of biologic agents has been observed during long-term
treatment of psoriasis.
Previous studies have had limited numbers of patients and short observation times
and showed conflicting data.

244 British Journal of Dermatology (2015) 172, pp244252 2014 British Association of Dermatologists
Biologic survival in psoriasis, R. Gniadecki et al. 245

What does this study add?


This is the largest study to date, comprising 1277 patients followed for up to
10 years.
Long-term drug survival depends on the drug (ustekinumab > adalimumab = inf-
liximab > etanercept), sex (men > women) and previous exposure to another bio-
logic.

Almost a decade of biologic drug use in dermatology has pro- trials) who received biologic treatment for psoriasis vulgaris
ven their usefulness in the management of moderate and severe in Denmark between March 2003 and June 2013. Us-
psoriasis. Unlike most traditional systemic therapies the biolo- tekinumab has been available in Denmark since April 2009, so
gics do not exhibit cumulative toxicity and therefore have an the observation time for this drug has been shorter than for
excellent safety profile in the long-term, continuous manage- the anti-tumour necrosis factor (TNF)-a agents. Eligibility for
ment of patients.1 Unfortunately, there are still significant gaps the biologic treatment for plaque psoriasis is regulated
in the understanding of the long-term efficacy of biologic by the national guidelines of the Danish Dermatological
drugs. Open label extension (OLE) studies have indicated that Society (http://2convert.dk/dds/wp-content/uploads/2012/
most patients are likely to maintain the effect over years.24 08/3bio_guides_dec_2011.pdf).5 Biologic treatments are
Unfortunately, the results are difficult to translate to clinical administered to the patients with moderate to severe psoriasis
decisions, as statistics in most OLE studies rely on the last- [PASI > 10 or Dermatology Life Quality Index (DLQI) > 10
observation-carried-forward principle and may significantly or affected body surface area > 10%] in whom treatments
overestimate the true long-term efficacy. Indeed, the real-life previously failed or who have contraindications to topical
observational data suggest that loss of efficacy of the biologic therapies, ultraviolet B phototherapy and methotrexate.
occurs in 1025% of patients annually.58 Another limitation Patients who refuse methotrexate must have documented con-
of the OLE studies is the choice of endpoint, which is usually traindication to or lack of efficacy of ciclosporin or acitretin.
Psoriasis Area and Severity Index (PASI) reduction in compari- Thus, according to the guidelines, patients with PASI < 10
son with the baseline PASI value before the administration of might be included, if they reported DLQI > 10 or if they
the biologic [usually PASI50 or PASI75 (reduction in PASI score switched from a conventional systemic therapy or another bio-
by 50% or 75%)]. However, there is ample evidence that the logic therapy which had had partial (yet insufficient) effect.
PASI reduction is not well correlated with patients perception The criteria of the short-term therapeutic success of the ther-
of treatment success and even patients who achieved PASI75 apy were reduction of PASI by 50% (PASI50) or absolute PASI
response do not consider this effect optimal.9,10 value < 5 or DLQI < 10 at 3 months (2 weeks) after the
DERMBIO is a national registry of patients treated with bio- initiation of treatment, but the long-term success criteria were
logic drugs in Denmark, which allows for long-term monitor- at the discretion of the attending physician and the patient
ing of treatment efficacy and safety.5 In our previous analysis and are not regulated by the guidelines. The choice of drug
we have proposed the drug survival rate (measured as a prob- was the decision of the physician, but for the patients with
ability to discontinue the drug) as a simple and clinically rele- concomitant psoriatic arthropathy (PsA) the guidelines sug-
vant measure of the treatment outcome.5 We have gested use of a TNF-a blocker rather than ustekinumab as first
documented that the main reason for drug discontinuation is choice.
loss of efficacy; this result has subsequently been confirmed
by independent studies.6,8,11,12
This paper provides a new analysis of the DERMBIO cohort, Data source and data extraction
now including 1277 patients treated with biologics (ada-
The DERMBIO database was established in 2007 to monitor
limumab, etanercept, infliximab and ustekinumab) over a 10-
the efficacy and side-effects of biologic drugs in Denmark.
year period. To our knowledge this is the largest dataset,
This registry is nationwide and includes all biologic treatments
which shows the real-life treatment outcomes in a cohort of
administered in academic hospital centres (88% of all treat-
patients in the whole country.
ment series) and in private clinics (22% of the treatment ser-
ies). Available data for biologic treatments that had been
Patients and methods
initiated before the launch of DERMBIO (n = 137 treatment
series) were added retrospectively to the registry. The aca-
Patient inclusion and exclusion
demic hospital centres reported 100% of the administered
Patients who were included in this analysis are real-life treatments series whereas the data for the coverage of the
patients (i.e. excluding the patients participating in the clinical treatments administered in private clinics has not been estab-

2014 British Association of Dermatologists British Journal of Dermatology (2015) 172, pp244252
246 Biologic survival in psoriasis, R. Gniadecki et al.

lished but is probably higher than 80%. In order to preserve 2013. In total 1867 treatment series were administered: 774
the maximal data integrity we therefore decided to include treatment series with adalimumab, 449 with etanercept, 253
only data reported from the hospital centres. with infliximab and 391 with ustekinumab. There were 436
Data in DERMBIO are organized as treatment sequences (ser- patients who received more than one treatment sequence with
ies) comprising a period of continuous treatment with a given a biologic.
biologic. Thus, one patient may receive several treatment Table 1 shows the basic patient characteristics as recorded
sequences of different durations. Data from the entire database during the first treatment sequence. The groups of patients
was extracted by the administrator (Zitelab Ltd, Frederiksberg, were defined by the biologic chosen for the first treatment
Denmark) to an Excel file, which for each treatment sequence sequence and they were comparable regarding age, male/
contained: (1) patients identification number, (2) sex, (3) female ratio, weight, disease duration, and the baseline values
age, (4) weight, (5) diagnosis and duration of psoriasis, (6) of PASI and DLQI. All groups had an overrepresentation of
identity of the biologic agent and number of the treatment male patients. The prevalence of PsA was high in the groups
sequence, (7) presence of PsA, (8) number of comorbidities, treated with anti-TNF-a agents, which probably reflected the
(9) diagnosis of comorbidities (hypertension, ischaemic heart selection of high-need patients for biologics. The frequency of
disease, hypercholesterolaemia, diabetes, nonmelanoma skin PsA was significantly lower in the ustekinumab group, reflect-
cancer, alcohol abuse, obesity), (10) date of treatment initia- ing the priority of the anti-TNF-a agents for patients with PsA
tion, (11) date of treatment discontinuation or last visit (in the in Danish clinical guidelines. Methotrexate was used as a con-
case of censored data), (12) reason for treatment discontinua- comitant therapy in 254% of cases, most commonly together
tion (categories: adverse event, lack of efficacy, patients deci- with infliximab (551%) and least frequently with us-
sion, lost to follow-up, other), (13) adverse events (categories: tekinumab (124%). A relatively high proportion of patients
infection, allergy or drug intolerance, skin rash, lupus like syn- had one or more comorbidities (arterial hypertension 234%,
drome, other), (14) severity of the adverse event (minor or obesity 232%, hypercholesterolaemia 150%, diabetes 101%,
major), (15) concomitant treatment with methotrexate. ischaemic heart disease 59%, alcohol abuse 40% or other/
In the present study we have included the treatment nonspecified 151%).
sequences, which fulfilled the following criteria: valid patient The short-term effect of treatment measured as the PASI
number enabling data verification, treatment with the cur- reduction after the initial 34 months of treatment was com-
rently approved biologics (adalimumab, etanercept, inflix- parable to what could be predicted from the clinical trials with
imab, ustekinumab) and minimum treatment duration of the biologics.13 The highest proportion of PASI75 responders
1 month. Interrupted series with the same biologic were (767%) was achieved for infliximab whereas the lowest
joined if the treatment break was < 1 month for adalimumab (538%) was recorded for etanercept. There was no statistical
and etanercept, 2 months for infliximab and 4 months for difference between adalimumab and ustekinumab in PASI75
ustekinumab. response rates (Table 1).

Statistical analysis Causes of drug discontinuation


Basic descriptive statistical analysis was done with Microsoft Of the total 1867 treatment series administered for 1 month
Excel (2011 MAC version 14.3.9; Microsoft Corp, Redmond, or longer, 772 treatment sequences (413%) were termi-
WA, U.S.A.) or GRAPHPAD PRISM version 5.00 for Mac nated. The major reason for treatment termination was a loss
(GraphPad Software, San Diego, CA, U.S.A.). For all other analy- of efficacy, which was highest for etanercept (416% of all
ses the data were exported from the Excel file to SPSS statistical treatment series) and lowest for ustekinumab (159%)
software (version 22 for Mac, IBM, Armonk, NY, U.S.A.) envi- (P < 0001, Chi-square test) (Fig. 1a). Rates of adverse
ronment. Drug survival analysis was done using Cox logistic events leading to discontinuation was highest for infliximab
regression with multiple covariates (described in Results). (146%) and lowest for ustekinumab (31%) (P < 0001,
Crude survival curves not adjusted for the covariates were com- Chi-square test). The leading causes were minor infections
pared with MantelCox statistics and shown as KaplanMeier (32%, 41 treatment series), which were mostly associated
plots. Odds ratios with 95% confidence intervals were calculated with adalimumab (463%; 25% of all administered treat-
as exp(B) values in SPSS using the proportional hazard model ment sequences) and infliximab (317%; 51% of treatment
for drug withdrawal. Frequency table comparisons were done series) and were relatively infrequent for etanercept (146%;
with Chi-square test. P < 005 was considered significant. 13% of treatment series) or ustekinumab (73%; 08% of
treatment series) (P = 0002, Chi-square test for the differ-
ence between the drugs). Other adverse events leading to
Results
discontinuation were: skin rash or aggravation of skin symp-
toms (12%: seven patients on adalimumab, three on etaner-
Patient characteristics
cept and four on infliximab); 56% were reactions
We have identified 1277 patients who received biologic treat- considered to be intolerance or allergy (six patients on inf-
ment for plaque psoriasis in Denmark between 2003 and liximab, one on adalimumab) and there was one case of

British Journal of Dermatology (2015) 172, pp244252 2014 British Association of Dermatologists
Biologic survival in psoriasis, R. Gniadecki et al. 247

Table 1 Patient characteristics on entry in the database (first biologic treatment)

Drug
Adalimumab Etanercept Infliximab Ustekinumab All
Number of patients (% total) 567 (444) 364 (285) 176 (138) 170 (133) 1277 (100)
Male/female (% male) 362/205 (638) 240/124 (659) 119/57 (676) 103/67 (606) 824/453 (645)
Agea 444 (134) 463 (150) 455 (139) 446 (147) 452 (142)
Weighta 874 (199) 886 (212) 920 (225) 896 (250) 886 (211)
Disease durationa 187 (122) 195 (128) 187 (134) 179 (134) 189 (126)
PsA (%) 216 (381) 144 (396) 77 (438) 24 (141) 461 (361)
DLQIa 126 (68) 119 (69) 139 (57) 115 (78) 125 (70)
Number of patients with comorbidities (%)
0 271 (478) 170 (467) 79 (449) 95 (559) 615 (482)
12 181 (319) 125 (343) 60 (341) 53 (312) 419 (328)
>2 27 (48) 20 (55) 21 (119) 24 (141) 92 (72)
Methotrexate (%) 124 (219) 82 (225) 97 (551) 21 (124) 324 (254)
PASI baselinea 125 (76) 126 (78) 158 (85) 114 (83) 128 (80)
PASI at 3 monthsa 30 (39) 49 (64) 29 (42) 27 (43) 35 (49)
PASI75 (% of subjects) 661 538b 767b 643 643

PsA, psoriatic arthropathy; DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index; PASI75, at least 75% improvement
in PASI score. aMean (SD). bChi-square significant; adalimumab vs. ustekinumab NS; adalimumab vs. etanercept P < 001; adalimumab vs.
infliximab P < 005.

lupus-like syndrome (08%: adalimumab). Other reasons for dominant factor leading to the long-term discontinuation of
discontinuation such as loss to follow-up, patient decision or the biologic.
other/unspecified were quite infrequent (Fig. 1). This pat- To further explore the differences in drug survival between
tern did not differ between the first treatment sequence in the naive patients and those who were re-treated, we com-
the biologic-naive patients and in the subsequent series of pared the adjusted and crude survival curves between these
re-treatment (Fig. 1b,c). groups (Fig. 2; Table 3). Although all drugs showed a trend
towards shorter survival in the non-naive patients (Table 3),
the significant difference was demonstrated only for us-
Predictive factors for drug survival
tekinumab and etanercept. Ustekinumab had lost its advantage
Previous analysis of the DERMBIO cohort suggested that in patients pre-treated with another biologic and its survival
except for the type of drug, the significant negative predictors was equal to that of adalimumab or infliximab, but was still
of drug survival were the previous failure of the biologic superior to that of etanercept.
(naive patients having longest survival) and female sex.5 These After previous exposure to a biologic there was a striking
findings could be reproduced in the current data set (Table 2). shortening of ustekinumab survival. This was surprising
Both forward and backward Cox regression modelling (likeli- because we originally assumed that the survival of us-
hood ratio and Wald test) confirmed a shorter drug survival tekinumab would not (or only slightly) be affected by the
in female patients and in those who were previously treated previous failure of the anti-TNF-a agent as the mechanism
with a biologic. However, the number of previous treatments of action of ustekinumab differs from the TNF-a blockers.
was not significant. Other nonsignificant covariates were: age, We therefore asked whether the effect of ustekinumab was
weight, duration of psoriasis, presence of PsA, baseline PASI better when given to the patients with a primary failure of
and DLQI, concomitant methotrexate, or number of co-mor- a TNF-a inhibitor. In our cohort 145 patients fulfilled
bidities. Comparison of the crude, unadjusted survival curves criteria of a primary lack of efficacy of a TNF-a blocker
with log-rank MantelCox test and the adjusted survival curves (discontinuation of the drug within the first 6 months of
(for the statistically significant covariates: sex and previous the first treatment sequence due to the lack of efficacy).
biologic treatment) confirmed that ustekinumab was the drug These patients were re-treated in the subsequent treatment
associated with the best chances of long-term survival sequences with adalimumab (n = 61), etanercept (n = 45),
(Fig. 2a, Table 2). Etanercept was associated with the shortest infliximab (n = 17) or ustekinumab (n = 22). In these
drug survival compared with any other drug (MantelCox test patients ustekinumab demonstrated similar survival times to
P < 0001, Cox regression P < 0001) (Fig. 2a, Table 2). The those of infliximab and adalimumab whereas etanercept had
same results were reproduced when the dataset included only a significantly shorter survival time (P < 001), when tested
the patients who discontinued the drug due to lack of efficacy by MantelCox test and the survival functions in the Cox
(not shown). This confirms that the loss of efficacy is the logistic regression model.

2014 British Association of Dermatologists British Journal of Dermatology (2015) 172, pp244252
248 Biologic survival in psoriasis, R. Gniadecki et al.

Table 2 Odds ratios for treatment termination. Data calculated from


(a) 80
Adverse event the Cox regression model using forward Wald method
% of treatment series Lost to follow-up
60
Lack of efficacy
95%
Other
40 Odds confidence P-
Patient decision
Covariate ratio interval value
20 Adalimumab vs. ustekinumab 177 139226 < 00001
Etanercept vs. ustekinumab 255 198329 < 00001
0 Infliximab vs. ustekinumab 199 150263 < 00001
<
ab

ab

ab
pt

Etanercept vs. adalimumab 142 120168 00001


ce
um

m
xi
er

nu
im

fli
Etanercept vs. infliximab 130 104161 002
an

ki
in
al

te
et
ad

us
Naive vs. previously exposed 124 105146 0011
(b) Male vs. female 151 131174 < 00001
100
Adverse event
% of treatment series

80 Lost to follow-up
Lack of efficacy
60 Other
Patient decision SAEs were recorded by the physicians as related or possibly
40
related to the treatment.
20

0 Discussion
ab

ab

ab
pt
ce
um

Long-term efficacy and survival of biologic drugs have previ-


xi
er

nu
im

fli
an

ki
in
al

te
et
ad

ously been reported for patients with psoriasis in a real-life


us

(c) setting by us and other investigators.58,11,12,14 The main


80
Adverse event strength of the present analysis is an unprecedentedly long
% of treatment series

Lost to follow-up
60 observation time of 10 years and a large number of patients
Lack of efficacy
Other
treated with each biologic (1277 patients vs. 119650 patients
40 in previously published studies). The DERMBIO registry is
Patient decision
prospective, nationwide and has a complete coverage of the
20
patients with psoriasis treated with the biologic drugs in the
0
hospital departments of dermatology in Denmark. This is
another important advantage of the current work, as previous
ab

ab

ab
pt
ce
um

studies originated from single centres7,8,11 or few centres,6


xi
er

nu
im

fli
an

ki
in
al

did not cover sufficient numbers of patients on each drug7,8,11


te
et
ad

us

or excluded subgroups of patients.6


Fig 1. Reasons for termination of biological treatment in all treatment Our initial study revealed that the discontinuation of the
series (a), in biologically naive patients (b) and in patients previously biologic drugs during long-term treatment is mainly driven by
exposed to a biologic (c). Data are shown as proportions of the the gradual loss of efficacy. Current analyses as well as other
treatment series for a given drug. independent studies6,11 confirm this conclusion. On average,
the median survival for the biologics in psoriasis was
47 months and 67% of all discontinuations were attributed to
loss of efficacy (Fig. 1). Adverse events accounted for only
Safety
97% of all drug discontinuations. Examination of the shape
Minor adverse events were relatively common and were of the survival curves in Figure 2 does not reveal any obvious
recorded in 1022 treatment sequences but they were the cause plateau in the time frame of this study. This suggests that the
of treatment termination in only 99 series (97%). As could loss of efficacy is a stochastic phenomenon, which happens at
be expected from the above-described pattern of adverse a relatively constant rate throughout the whole treatment per-
events leading to termination, 438% were nonserious infec- iod. Similar shapes of the curves were reported for the drug
tions, 86% comprised skin rash or exacerbation of skin symp- discontinuation rates for patients with psoriatic arthritis and
toms, 17% were allergic reactions or drug intolerance, 06% rheumatoid arthritis. Further research is needed to determine
lupus-like syndrome. The rest (453%) were not classified. the cause of the loss of efficacy. Induction of anti-drug anti-
Serious adverse events (SAEs) were listed separately bodies, compensatory induction of other proinflammatory
(Table 4). In total 33 SAEs were recorded in the period on cytokines, or interindividual variability in drug metabolism
the four biologic drugs (adalimumab 15, infliximab 6, can be suggested as possible causes.
ustekinumab 2 and eternacept 10). Among these, nine were The statistically significant predictors of drug discontinua-
infections, nine were different kinds of common neoplasms tion were the type of biologic agent, patients sex and previ-
and three were allergic reactions to the treatment. Twenty-two ous exposure to a biologic. Ustekinumab appeared to have

British Journal of Dermatology (2015) 172, pp244252 2014 British Association of Dermatologists
Biologic survival in psoriasis, R. Gniadecki et al. 249

(a) (b)

(c) (d)

(e) (f)

Fig 2. Drug survival for the biologic agents in psoriasis. (a, b) Drug survival for all treatment sequences from the DERMBIO database (n = 1867).
Data include 774 adalimumab treatment series (n = 307 terminated sequences), 449 etanercept series (n = 257 terminated), 253 infliximab series
(n = 122 terminated) and 391 ustekinumab series (n = 86 terminated). The Cox model in panel (a) shows theoretically predicted survival curves
adjusted for sex and previous biologic treatment whereas panel (b) shows the actual survival curves (KaplanMeier analysis). Analogous analysis
for the biologically naive patients (first treatment sequence; n = 1277, 544 terminated sequences) (c, d) and for the patients pre-treated with at
least one biologic (n = 576; 221 terminations) (e, f).

2014 British Association of Dermatologists British Journal of Dermatology (2015) 172, pp244252
250 Biologic survival in psoriasis, R. Gniadecki et al.

Table 3 Comparison of naive and biologic-exposed patients

Estimated survival time (months)


Nave patients Previously exposed to a biologic All patients
Druga Median (SE) 95% CI Median (SE) 95% CI Median (SE) 95% CI
c
Adalimumab 59 (81) 431749 50 (82) 340660 59 (69) 456724
Etanercept 33 (41)b 250410 18 (23)b 136224 30 (25)b 251349
Infliximab 47 (48) 376564 36 (100) 164556 44 (56)c 330549

SE, standard error; CI, confidence interval. a50% survival not computable for ustekinumab. bSignificant difference with adalimumab
(P < 0001) and infliximab (P = 0008) (logrank MantelCox test). cWorse than ustekinumab P < 0001.

Table 4 Number of serious adverse events

Serious adverse
events Adalimumab Infliximab Eternacept Ustekinumab Total
Total 15 6 10 2 33
Infection 6 2 1 0 9
Cancer 4 2 2 1 9
Cardiovascular 2 1 3 0 6
Other 3 1 4 1 9
Related or possibly related to treatment 9 3 10 0 22

superior capacity to maintain the efficacy long-term, even after These methodological differences may help to explain the
compensation for other covariates. However, it is important to discrepancies between the findings in this study and the
notice that the observation time for ustekinumab was only results from other registries. Esposito et al.6 published their
5 years. Etanercept was associated with the shortest drug sur- findings from the Italian cohort documenting a superior drug
vival. There were no statistical differences between ada- survival of etanercept, which is the opposite of our conclu-
limumab and infliximab. sions. However, unlike our registry where all biologically trea-
These differences are of potential clinical importance but ted patients with psoriasis are followed, the study of Esposito
should be interpreted with caution. The relative capacity of et al. excluded the patients in whom the biologics were pre-
the biologic to retain the efficacy long term depends not only scribed outside the protocol and the patients who had previ-
on the inherent property of the drug but also on the treatment ously been exposed to TNF-a inhibitors or who received
schedule, dosing and the reasons that govern the decisions to combination therapies. Only patients with standard dose regi-
switch to another therapy. Dose adjustment of biologics is a mens were included. It is therefore conceivable that there
common clinical practice in Denmark. We have previously were important differences in the characteristics of patient
shown that therapeutic effect of infliximab can be recaptured populations between our cohort and the study of Esposito
in a clinical setting by the increase of the dose and shortening et al. Additionally, this study employed pre-defined objective
intervals between injections.15 Similarly, doubling of the dose criteria of treatment response (PASI50 for the primary
of ustekinumab helps to maintain optimal therapeutic effect in response and loss of PASI50 for the secondary inefficacy) and
a number of patients.16 Unfortunately, the precise dosing the majority (598%) received etanercept (in contrast to our
schedule is very difficult to analyse, as many dose adjustments cohort where only 285% was treated with this drug). How-
are transient and have not been adequately reported to our ever, a significant proportion of patients do not consider
registry. Secondly, it is important to emphasize that in the PASI50 as optimal and will require further treatment optimiza-
DERMBIO registry the decision of drug discontinuation is tion.9,10 Moreover, the median survival times for etanercept
based on a clinical judgement of its efficacy rather than objec- reported by Esposito et al. (approximately 2000 days,
tive measurement of disease activity. It is well established that 66 months) does not only disagree with our findings but also
PASI correlates only poorly with the physicians and patients with the longitudinal studies of van den Reek et al.8,12 who
perception of the severity of disease.9,10 The perception of reported median survival of etanercept in Dutch cohorts of
treatment success correlates very poorly with PASI reduction approximately 3640 months (after exclusion of the clinical
or absolute PASI values but most patients will consider psoria- trial patients), a number that is within our confidence interval
sis PASI values higher than 45 as not satisfactorily treated.16 of 2541 months.
Thus, our data may not be directly comparable with the regis- The median drug survival of infliximab in the study of Es-
tries in which the objective measurements of psoriatic activity posito et al.6 was approximately 42 months and was in agree-
dictate the choice of treatment. ment with our data (44 months). However, the median

British Journal of Dermatology (2015) 172, pp244252 2014 British Association of Dermatologists
Biologic survival in psoriasis, R. Gniadecki et al. 251

survival of adalimumab was very short (23 months), which the patients who switched the biologic agent had a median
was less than half of our value of 59 months and the drug survival of 13 years vs. 22 years for the patients who
56 months reported from a Spanish cohort by L opez-Ferrer remained on the same therapy.20 Interestingly, the number of
et al.7 It can therefore be concluded that our data are sup- the previously used biologics was not a significant factor for
ported by the independent studies from the Dutch and Spanish drug survival in our cohort.
cohorts and argue against the generalizability of the findings There are various possible explanations for the shortening
of Esposito et al. on the patients in a real-life setting. of drug survival after switching from one biologic to another.
The novel aspect of our current study is the inclusion of us- According to the immunization theory, the exposure to a bio-
tekinumab, which is characterized by long treatment intervals logic causes production of anti-drug antibodies that would
of 12 weeks and a different mechanism of action than ada- impair the efficacy of the next drug. These anti-drug antibod-
limumab, etanercept or infliximab. In accordance with our ies are predominantly anti-idiotypic, which implies that they
previous pilot study17 and a recent small observational study will not react against a therapeutic antibody binding to an
by van den Reek et al.,12 ustekinumab showed a clear superi- unrelated target.21,22 However, we have clearly demonstrated
ority, surpassing any other anti-TNF-a agent in terms of long- that the survival of ustekinumab [anti-p40 interleukin (IL)-
term efficacy. This finding was not entirely unexpected as the 12/23] is impaired following previous exposure to anti-TNF-
5-year follow-up of 3117 patients in the open-label extension a agents targeting a structurally unrelated TNF-a. Another
study has been characterized by a very low drop-out rate of putative explanation is different rates of drug catabolism influ-
6% per year and the 75% patient retention at 4 years.4,16 Our encing drug levels. Studies on infliximab showed a good cor-
analysis showed that 819% of patients who received us- relation between serum drug levels and efficacy. It is
tekinumab as their first biologic remained on therapy 4 years conceivable that some patients have a higher rate of antibody
later. For all patients (biologically naive and retreated) the catabolism, which is independent of its specificity. However,
retention rate was 70% at 4 years. the analysis of the survival curves do not show a clear plateau,
The reason for this excellent long-term efficacy has not which suggests that the loss of efficacy appears in a stochastic
been elucidated, but cannot be explained by the short-term manner during long-term treatment. A third possible explana-
efficacy, which was comparable with that of infliximab or tion is an immunological reorchestration. It is conceivable that
adalimumab. One of the explanations might be that us- a long-term suppression of a single cytokine will cause an
tekinumab is more often dose adjusted than adalimumab induction of other proinflammatory cytokines with the redun-
(dose increase from 45 to 90 mg) due to flat pricing of us- dant function. This theory would explain the loss of efficacy
tekinumab in Denmark. It has been shown that such dose of ustekinumab in patients previously exposed to anti-TNF-a
adjustment will recapture efficacy in approximately 45% of agents provided that TNF-a and IL-12/23 proinflammatory
patients who would otherwise have lost the clinical signalling pathways are interconnected. Our observation that
response.18 the patients who do not primarily respond to anti-TNF-a
Patients sex and previous exposure to a biologic were other agents show a diminished response to ustekinumab is also
significant predictors of drug survival. A striking observation compatible with this theory.
that male patients demonstrate better long-term drug survival In summary, our data clearly show that the long-term treat-
has been reported by our group and confirmed by others.6,8 ment success is mainly limited by the progressive loss of drug
Shorter drug survival in women is true for all biologic agents efficacy, which in turn seems to be dissociated in its short-
including ustekinumab and has also been reported in the rheu- term effect. Long-term efficacy seems to be further impaired
matological literature for psoriatic arthritis and rheumatoid in patients who switched from one biologic to another. There
arthritis.19,20 To our knowledge there is no satisfactory expla- is a need for better understanding of the factors affecting
nation for this finding but because this phenomenon is long-term drug survival to address long-term treatment opti-
observed across different indications and biologic agents it is mization in psoriasis.
likely to have a biological rather that psychological explanation.
The negative effect of previous biologic therapy is an inter-
esting and clinically important phenomenon. All biologics References
tended to have a shorter drug survival in patients who previ- 1 Rustin MHA. Long-term safety of biologics in the treatment of
ously received and discontinued another biologic, but the moderate-to-severe plaque psoriasis: review of current data. Br J
effect was most pronounced for ustekinumab and etanercept. Dermatol 2012; 167 (Suppl.):311.
As with the biologically naive patients the main reason was 2 Gordon K, Papp K, Poulin Y et al. Long-term efficacy and safety of
loss of efficacy. The data are supported by Esposito et al.,6 adalimumab in patients with moderate to severe psoriasis treated
who reported that the switch from another anti-TNF-a agent continuously over 3 years: results from an open-label extension
study for patients from REVEAL. J Am Acad Dermatol 2012; 66:241
to etanercept was associated with a dramatic reduction of drug
51.
survival to 179 months, a figure that is almost identical to 3 Papp KA, Poulin Y, Bissonnette R et al. Assessment of the long-
our results (180 months). Lopez-Ferrer et al.7 found a signifi- term safety and effectiveness of etanercept for the treatment of
cant reduction of adalimumab survival in patients with prior psoriasis in an adult population. J Am Acad Dermatol 2010; 66:
exposure to another anti-TNF-a agent. In psoriatic arthritis, e3345.

2014 British Association of Dermatologists British Journal of Dermatology (2015) 172, pp244252
252 Biologic survival in psoriasis, R. Gniadecki et al.

4 Kimball AB, Gordon KB, Fakharzadeh S et al. Long-term efficacy of 14 Papoutsaki M, Talamonti M, Giunta A et al. The impact of method-
ustekinumab in patients with moderate-to-severe psoriasis: results ological approaches for presenting long-term clinical data on esti-
from the PHOENIX 1 trial through up to 3 years. Br J Dermatol mates of efficacy in psoriasis illustrated by three-year treatment
2012; 166:86172. data on infliximab. Dermatology 2010; 221(Suppl. 1):437.
5 Gniadecki R, Kragballe K, Dam TN, Skov L. Comparison of drug 15 Mehren CR, Gniadecki R. Dose-creep of infliximab during psoriasis
survival rates for adalimumab, etanercept and infliximab in treatment: an observational study. Acta Derm Venereol 2012; 92:355
patients with psoriasis vulgaris. Br J Dermatol 2011; 164:10916. 7.
6 Esposito M, Gisondi P, Cassano N et al. Survival rate of anti- 16 Kimball AB, Papp KA, Wasfi Y et al. Long-term efficacy of us-
TNF alpha treatments for psoriasis in routine dermatological tekinumab in patients with moderate-to-severe psoriasis treated for
practice: a multicenter observational study. Br J Dermatol 2013; up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol
169:66672. 2013; 27:153545.
7 Lopez-Ferrer A, Vilarrasa E, Gich IJ, Puig L. Adalimumab for the 17 Clemmensen A, Spon M, Skov L et al. Responses to ustekinumab in
treatment of psoriasis in real life: a retrospective cohort of 119 the anti-TNF agent-nave vs. anti-TNF agent-exposed patients with
patients at a single Spanish centre. Br J Dermatol 2013; 169:11417. psoriasis vulgaris. J Eur Acad Dermatol Venereol 2011; 25:103740.
8 Van den Reek JMPA, van L umig PPM, Driessen RJB et al. Determi- 18 Reich K, Puig L, Paul C et al. One-year safety and efficacy of us-
nants of drug survival for etanercept in a long-term daily practice tekinumab and results of dose adjustment after switching from
cohort of patients with psoriasis. Br J Dermatol 2014; 170:41524. inadequate methotrexate treatment: the TRANSIT randomized trial
9 Mattei PL, Corey KC, Kimball AB. Psoriasis Area Severity Index in moderate-to-severe plaque psoriasis. Br J Dermatol 2014;
(PASI) and the Dermatology Life Quality Index (DLQI): the corre- 170:43544.
lation between disease severity and psychological burden in 19 Hetland ML, Christensen IJ, Tarp U et al. Direct comparison of
patients treated with biological therapies. J Eur Acad Dermatol Venereol treatment responses, remission rates, and drug adherence in
2014; 28:3337. patients with rheumatoid arthritis treated with adalimumab, eta-
10 Mehren CR, Clemmensen A, Dall AB-H et al. Essential factors influ- nercept, or infliximab: results from eight years of surveillance of
encing health-related-quality of life in psoriasis. J Drugs Dermatol clinical practice in the nationwide Danish DANBIO registry. Arthritis
2014; 13:24650. Rheum 2010; 62:2232.
11 Menting SP, Sitaram AS, Bonnerjee-van der Stok HM et al. Drug 20 Glintborg B, Ostergaard M, Krogh NS et al. Clinical response, drug
survival not significantly different between biologics in patients survival, and predictors thereof among 548 patients with psoriatic
with psoriasis vulgaris: a single-centre database analysis. Br J Derma- arthritis who switched tumor necrosis factor a inhibitor therapy:
tol 2014; 171:87583. results from the Danish Nationwide DANBIO registry. Arthritis
12 van den Reek JM, Zweegers J, Kievit W et al. Happy drug survival Rheum 2013; 65:121323.
of adalimumab, etanercept and ustekinumab in psoriasis in daily 21 Wolbink GJ, Aarden LA, Dijkmans BAC. Dealing with immunoge-
practice care results from the BioCAPTURE network. Br J Dermatol nicity of biologicals: assessment and clinical relevance. Curr Opin
2014; 171:118996. Rheumatol 2009; 21:21115.
13 Reich K, Burden AD, Eaton JN, Hawkins NS. Efficacy of biologics 22 Van Schouwenburg PA, van de Stadt LA, de Jong RN et al. Ada-
in the treatment of moderate to severe psoriasis: a network meta- limumab elicits a restricted anti-idiotypic antibody response in
analysis of randomized controlled trials. Br J Dermatol 2012; autoimmune patients resulting in functional neutralisation. Ann
166:17988. Rheum Dis 2013; 72:1049.

British Journal of Dermatology (2015) 172, pp244252 2014 British Association of Dermatologists