Clinical and epidemiological research
EXTENDED REPORT
An additional
supplementary table is
published online only. To view
this le please visit the journal
online (http://dx.doi.org/
10.1136/annrheumdis-2012-
201933)
For numbered afliations see
end of article.
Correspondence to
Dr Bente Glintborg,
Department of Rheumatology,
Gentofte University Hospital,
Niels Andersensvej 65,
Hellerup 2900, Denmark;
glintborg@dadlnet.dk
Received 26 April 2012
Accepted 19 July 2012
Published Online First
31 August 2012
Ann Rheum Dis 2013;72:11491155. doi:10.1136/annrheumdis-2012-201933
Clinical response, drug survival and predictors
thereof in 432 ankylosing spondylitis patients after
switching tumour necrosis factor inhibitor therapy:
results from the Danish nationwide DANBIO registry
Bente Glintborg,1,2 Mikkel stergaard,3 Niels Steen Krogh,4 Ulrik Tarp,5 Natalia Manilo,6
Anne Gitte Rasmussen Loft,7 Annette Hansen,1 Annette Schlemmer,8 Victoria Fana,9
Hanne M Lindegaard,10 Henrik Nordin,11 Claus Rasmussen,12 Leif Ejstrup,13
Dorte Vendelbo Jensen,14 Peter Mosborg Petersen,15 Merete Lund Hetland2,3
ABSTRACT
Objective To investigate frequencies and reasons for
switching, treatment responses and drug survival in
patients with ankylosing spondylitis (AS) switching
tumour-necrosis-factor- inhibitor (TNFi) treatment in
routine clinical care.
Methods AS patients were identied in the Danish
nationwide DANBIO registry. Disease activity, treatment
responses (50% or 20 mm reduction in Bath AS Disease
Activity Index (BASDAI)), duration and rates of drug
survival and predictors thereof were studied in patients
receiving 2 different biological drugs.
Results Of 1436 AS patients starting TNFi treatment,
432 patients (30%) switched to a second and 137 (10%)
to a third biological drug. Compared with non-switchers,
switchers were more frequently women (33%/22%), had
shorter disease duration (3 years/5 years) and higher
BASDAI (62(5276) mm/56(4369) mm (median
(interquartile-range))), Bath AS Functional Index (BASFI)
(54(3971) mm/47(3165) mm) and visual-analogue-
scale (VAS) global, pain and fatigue scores when they
started the rst TNFi (all p<0.01). Main reason for
switching was lack of response (56%). During the rst,
second and third treatment BAS- and VAS scores had
decreased after 6 months treatment (all p<0.05).
Median drug survivals were 3.1, 1.6 and 1.8 years
respectively ( p<0.001). After 2 years of treatment 52%
of switchers and 63% of non-switchers had achieved
response (number needed to treat 1.9 and 1.6,
respectively, p=0.01). Drug survivals were similar
regardless of the reason for switching. Male gender and
low BASFI predicted drug survival of the second TNFi.
Conclusions Nearly one-third of AS patients in clinical
practice switched biological treatment. Response rates
and drug survivals were lower among switchers,
however, half of switchers achieved treatment response.
INTRODUCTION
The benecial effect of tumour-necrosis-factor-
-inhibitor (TNFi) treatment in ankylosing spon-
dylitis (AS) has been documented in several
randomised trials.13 However, some patients experi-
ence lack of treatment effect (LOE) and some
patients terminate treatment due to side effects.
In Denmark, four TNFi are currently marketed
for the treatment of AS (iniximab, etanercept,
adalimumab and golimumab). The drugs have dif-
ferent chemical structures, routes of administration
and pharmacokinetics.4 Thus, if a patient fails to
achieve adequate response during the rst treat-
ment or experiences adverse events (AE), a switch
to a second TNFi seems appealing.
Among patients with rheumatoid arthritis (RA),
switching has become daily practice510 and approxi-
mately 55% of RA switchers achieve ACR20
response.11 However, the rate and success of switch-
ing may be different in patients with AS.12 13
Currently, experiences from switching in
patients with AS mainly originate from one large
open label trial14 and several smaller observational
studies including few treatment centres or less
than 50 switch episodes.8 12 1522
The Danish nationwide DANBIO registry now
includes up to 10 years of prospective follow up of
patients with inammatory arthritis treated with
biologicals in routine care.23 We have previously
described treatment response and predictors thereof
in AS patients receiving the rst TNFi treatment.24
The aims of the present study were to investigate
frequencies and reasons for switching, treatment
responses, drug survivals and predictors thereof
among patients switching TNFi treatment.
PATIENTS AND METHODS
The Danish DANBIO-registry is a nationwide regis-
try that was commenced in year 2000 and approved
as a clinical quality registry in 2006. DANBIO
covers >90% of adults treated with biologics due to
rheumatic disease in routine care.2527 According to
Danish legislation, any registration and publication
of data from clinical registries does not require
patient consent or approval by Ethics Committees.
Biological treatment courses initiated before 1
January 2011 were included in the present study
and follow-up was until 20 April 2011. By 1
January 2011, 2039 patients with a diagnosis of AS
according to specialists in rheumatology had been
registered. It is not explicitly stated in DANBIO
how individual patients fulll the diagnostic
1149
 Clinical and epidemiological research

Table 1 Baseline demographics and disease activity when patients Treatment response
started the first tumour necrosis factor inhibitor Disease activity was evaluated by the CRP, VAS pain, fatigue
Non-switchers Switchers p Value
and global, BASDAI, BASFI and BASMI-scores 0, 3 and
N=1004 N=432 6 months after initiation of therapy.
Treatment response during each treatment course was evalu-
Age 41 (3351) 41 (3249) 0.4 ated as a reduction in BASDAI of at least 50% or >20 mm
Women, n (%) 218 (22) 142 (33) 0.0001 (BASDAI 50%/20 mm response).1 28 We classied patients as
Disease duration (years) 5 (114) 3 (111) 0.01 responders if they achieved a sustained BASDAI 50%/20 mm
Symptom duration (years) 14 (622) 11 (419) 0.0001 response (yes/no) at both the 3 and 6-months visits compared
Use of methotrexate, n (%) 262 (26) 157 (36) 0.0001 with the BASDAI registration at 0 months. Thus only patients
CRP (mg/l) 13 (527) 13 (526) 0.4 treated >3 months were included in this analysis. The individual
VAS fatigue (mm) 65 (4678) 74 (5687) 0.0001 components of the BASDAI score were not registered in DANBIO
VAS global (mm) 66 (4679) 72 (5785) 0.0001 until year 2008, and therefore Assessment of SpondyloArthritis
VAS pain (mm) 62 (4477) 70 (5181) 0.0001 international Society (ASAS) response is not reported.
BASDAI (mm) 56 (4369) 62 (5276) 0.0001 The overall long-term treatment response was evaluated at the
BASFI (mm) 47 (3165) 54 (3971) 0.0001 2-year visit (dened as the rst visit >104 weeks after initiating
BASMI 40 (2060) 40 (2060) 0.9 the rst TNFi). This time point was chosen arbitrarily to allow for
Mann-Whitney and 2 tests. Numbers are median (quartiles) unless otherwise an acceptable number of switch episodes without excluding too
stated. many patients with insufcient follow-up time. The BASDAI
BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath
Ankylosing Spondylitis Function Index; BASMI, Bath Ankylosing Spondylitis
50%/20 mm response at the 2-year visit was compared with the
Metrology Index; CRP, C reactive protein; VAS, visual analogue scale. baseline BASDAI at the rst treatment course, irrespective of
switch episodes in the meantime. Thus, only patients with a regis-
tration of BASDAI at baseline and follow-up for 2 years were
criteria for AS. Patients with psoriatic arthritis were excluded included in this analysis (609 patients). Also, the proportion of
from this analysis. We excluded 518 AS patients only treated patients with BASDAI <40 mm at the 2-year visit was evaluated.
with disease-modifying anti-rheumatic drugs (DMARDs), 84 In the subgroup of patients with available ASDAS,29 30 disease
patients treated with biologicals as part of clinical trials, and activity was reported as the median ASDAS and the proportion
one patient who did not receive TNFi as the rst biological. of patients attaining ASDAS <2.1 (inactive/moderate disease
Thus, 1436 biologically nave patients, who had been registered activity) at the latest visit registered after 2 years follow-up.
in DANBIO from the time of initiation of the rst TNFi were
included. Of these, a subgroup of 432 patients (switchers) had
Statistics
received treatment with two different biological drugs (TNFi
Statistical analyses were performed by SPSS (V.16.0, SPSS Inc.,
or other) during follow-up (table 1). The total number of treat-
Chicago, Illinois, USA) and SAS software (V.9.0, SAS Institute
ment courses was 2061.
Inc, Cary, North Carolina, USA). Demographic and descriptive
Axial disease activity was assessed by Bath AS Disease
data are presented by medians/IQR. Groups were compared by
Activity Index (BASDAI), Bath AS Function Index (BASFI),
non-parametric testing (unpaired data: 2 and Mann-Whitney
Bath AS Metrology Index (BASMI) and thorax excursion range
tests, paired: Wilcoxon signed ranks test). The proportion of
(introduced in year 2003). C reactive protein (CRP) level
patients achieving treatment responses were expressed as
(normal range 10 mg/l), visual analogue scales (VAS) for pain,
Number-Needed-to-Treat (NNT) calculated as the reciprocal
global and fatigue scores were also registered. Since year 2010
value of response rates. In all statistical tests, a p value <0.05
the AS Disease Activity Score (ASDAS) was registered. Data
was considered statistically signicant.
collection occurred at minimum biannually.
Kaplan Meyer plot and log rank test were used to visualise
Queries were sent to the hospitals regarding treatment series
drug survival. Unadjusted/univariate and multvariate Cox
with incomplete follow-up. All calculations were based on
regression analysis with HR were used for the identication of
observed data and no imputation of missing data was per-
factors associated with drug survival of the second treatment
formed. All observations were censored at 20 April 2011.
course. Logistic regression analyses and OR were used to iden-
tify factors associated with BASDAI 50%/20 mm response. In
Drug adherences
the regression analyses, patient age, baseline CRP, BASDAI,
Drug survival was calculated as the number of days individual
BASFI, BASMI and VAS scores were included as continuous
patients maintained treatment with the drug. Start date was the
variables whereas gender, type of TNFi (current and previous
date of the rst given dose and stop date was the date of the rst
treatment), use of methotrexate (yes/no) and reason for discon-
missed dose. Temporary treatment interruptions (eg, due to
tinuation of the rst TNFi (AE/LOE/other) were included as
infections or surgery) of <3 months duration were allowed. If a
categorical variables. The variables with the highest p value
patient restarted treatment with the same biological drug after
were excluded stepwise (backward selection) leaving only stat-
>3 months treatment interruption, the second treatment course
istically signicant variables in the nal model.
with the drug was deleted from the dataset (62 cases).
In the following, unless otherwise stated, the term baseline is
The reasons for drug discontinuation are registered in pre-
used to describe disease activity upon starting the individual
specied categories: LOE, AE, pregnancy, surgery, infections, loss
treatment course.
to follow up and other. In the following, switching-AE denotes
switching due to side effects, infection, death or cancer.
Switching-LOE denotes switching due to lack/loss of effect. RESULTS
Switching-other denotes switching due to any other cause (preg- Baseline characteristics and patient disposition
nancy, surgery, lost to follow up, disease remission) or several Among the included 1436 patients, 360 (25%) were women
reasons for drug discontinuation. and median age was 41 years (IQR 3350 years). Median

1150 Ann Rheum Dis 2013;72:11491155. doi:10.1136/annrheumdis-2012-201933

 Clinical and epidemiological research

Figure 1 Flow -chart of treatment course 1,2 and 3 and reasons for drug discontinuation (n= 1,436). Numbers show the number of patients LOE:
Lack of effects, AE: adverse events

follow-up time was 2.4 years (IQR 1.04.8 years). The patient patients), iniximab-etanercept (88 patients), adalimumab-
ow is outlined in gure 1. When data were censored, 432 etanercept (84 patients), etanercept-adalimumab (36 patients).
patients (32%) had switched treatment and 773 patients were Baseline iniximab doses among patients starting iniximab as
still treated with the original TNFi. Switchers were more fre- the rst, second and third treatment were 296 mg (3.9 mg/kg),
quently women, had shorter disease duration, were more fre- 364 mg (4.6 mg/kg) and 366 mg (5.0 mg/kg), respectively. Similarly,
quently treated with methotrexate and had higher VAS scores, the average doses at the latest registered visit were 324 mg (4.2 mg/
BASFI and BASDAI compared with non-switchers when they kg), 382 mg (4.9 mg/kg) and 390 mg (5.4 mg/kg), respectively. At
started the rst TNFi (table 1). More non-switchers who con- the latest visit, 21% of patients received iniximab every 6 weeks,
tinued treatment vs non-switchers who stopped treatment 11% every 7 weeks and 56% every 8 weeks. Baseline use of metho-
without starting a new TNFi, were men (80 vs 71%, p=0.002), trexate was more frequent among iniximab users and patients
but baseline disease activities were similar in the groups (all with peripheral joint disease (both p<0.01, data not shown).
p>0.05, data not shown). A total of 231 patients stopped the rst TNFi without starting a
The most prevalently used rst line drug was iniximab in new. The main reason for switching was LOE (240 patients, 56%
year 20012008 and adalimumab in year 20092010. of switchers) or AE (118 patients, 27%). Among the 432 patients
Adalimumab was the most frequently used second (46%) and who started treatment with a second biological, 137 switched to a
third line (31%) treatment (table 2). Biologicals other than third (32%), 217 patients continued treatment, and 78 patients
TNFi were only initiated in 19 of 2061 treatment series and stopped without starting a new. The main reason for switching to
will not be discussed further. The most frequent combinations a third biological was LOE (86 patients, 63% of switchers) (gure
of rst and second TNFi were: iniximab-adalimumab (161 1). Similarly, 39/137 patients (28%) switched to a fourth biological,
and 12/39 patients (31%) switched to a fth. Among the 432
switchers, baseline disease activity was similar irrespective of the
Table 2 Number of treatment courses according to biological drug reason for switching (see supplementary table S1).
Treatment course number
Biological drug Total (%) 1* 2* 3 4, 5, 6, 7 Drug survival
Drug survival decreased after switching ( p<0.001) (gure 2).
Adalimumab 781 (38) 532 (37) 197 (46) 42 (31) 10 (18)
Median drug survival of the rst TNFi among switchers was
Etanercept 452 (22) 231 (16) 172 (40) 40 (29) 9 (16)
0.7 years (95% CI 0.6 to 0.8 years).
Infliximab 741 (36) 653 (45) 42 (10) 37 (27) 9 (16)
Golimumab 59 (3) 20 (1) 15 (3) 9 (7) 15 (27)
Certolizumab 9 (0) 0 (0) 1 (0) 3 (2) 5 (9) Treatment response
Rituximab 8 (0) 0 (0) 3 (1) 2 (1) 3 (5) Most scores decreased after 3 and 6 months treatment during
Tocilizumab 4 (0) 0 (0) 0 (0) 2 (1) 2 (4) the rst, second and third treatment course (table 3). For
Abatacept 5 (0) 0 (0) 1 (0) 1 (1) 3 (5) switchers, baseline CRP was signicantly lower at the second
Anakinra 1 (0) 0 (0) 0 (0) 1 (1) 0 (0) and third treatment course compared with the rst ( p<0.05)
Not stated 1 (0) 0 (0) 1 (0) 0 (0) 0 (0) (gure 3). Baseline BASDAI and VAS global were signicantly
Total 2061 (100) 1436 (100) 432 (100) 137 (100) 56 (100) lower at the second treatment course compared with the rst
( p<0.001). For switchers, the delta values for the decrease in
Number of patients, number in brackets show percentages of total.
*Drug combinations (first-second drug): adalimumab (ada)-etanercept (eta) 84
CRP, BASDAI and VAS global between baseline and 6 months
patients, ada-infliximab (ifx) 31, ada-golimumab (gol) 6, ifx-ada: 161, ifx-eta 88, were similar at the second and third treatment course com-
ifx-gol 6, eta-ada: 36, eta-ifx: 11, eta-gol: 3 patients. pared with the rst (all p>0.05) (gure 3).

Ann Rheum Dis 2013;72:11491155. doi:10.1136/annrheumdis-2012-201933 1151

 Clinical and epidemiological research
Figure 2 Drug adherences by treatment course. Kaplan Meyer drug survival curves. The table below show the number of patients still treated at
the corresponding time points, the proportion of patients maintaining treatment after 2 years and the median drug survival. This gure is only
reproduced in colour in the online version.
During the rst treatment course, the proportion of patients
achieving BASDAI 50%/20 mm response within 6 months was 54%
(NNT=1.9). Corresponding rates during the second and third treat-
ment course were 37% (NNT=2.7) and 30% (NNT=3.4).
At the 2-year visit, 52% of switchers (NNT=1.9) and 63% of
non-switchers (NNT=1.6) (p=0.01) had a BASDAI 50%/20 mm
response (compared with the baseline visit of the rst TNFi)
and 54% of switchers (NNT=1.9) and 79% (NNT=1.3) of non-
switchers (p<0.0001) had a BASDAI <40 mm. Switchers had
received a median of two biological drugs (IQR 22).
Among patients treated 2 years, 316 patients had an avail-
able ASDAS-score at their latest visit. The proportion of
patients with ASDAS<2.1 was 37% among switchers and 71%
of non-switchers ( p<0.001). Median ASDAS among switchers
and non-switchers were 2.5 (IQR 1.83.5) and 1.6 (1.02.3),
respectively.
Predictors of drug survival and response during the second
treatment course
In univariate Cox regression, drug survival of the second bio-
logical was longer in men ( p=0.03), patients treated with adali-
mumab ( p=0.03), patients previously treated with iniximab
( p=0.004) and patients with lower BASFI ( p=0.03). Baseline
CRP, BASDAI, BASMI and VAS-scores, age, use of methotrexate
and reason for withdrawal of the rst TNFi were not statistic-
ally signicant. In multvariate Cox regression, predictors of
longer drug survival were male gender (HR 1.76 (95% CI 1.2 to
2.5), p=0.002) and low baseline BASFI (HR1.07/cm (1.01.15),
p=0.046), whereas type of TNFi (current or previous), reason
for withdrawal of rst TNFi, use of methotrexate, age, CRP,
BASMI, BASDAI and VAS scores at the start of the second
treatment were not predictive.
Predictors of BASDAI 50%/20 mm response during the second
treatment course were higher CRP at baseline (OR 1.03/mg/l
(95% CI 1.0 to 1.05), p=0.02), lower VAS fatigue (0.6/cm (0.5
1152
0.9), p=0.008), and lower BASFI (0.6/cm(0.20.8), p=0.001)
(multiple logistic regression analysis corrected for baseline
BASDAI). Type of TNFi (current or previous), reason for with-
drawal of rst TNFi, gender, age, BASMI, VAS global, VAS pain
and age were not signicant.
DISCUSSION
In this study of 1432 patients with AS we found that almost
one third switched TNFi during up to 10 years of follow-up.
Switchers were more frequently women and patients with
high baseline subjective disease activity. The main reason for
switching was LOE. The disease activity decreased signicantly
during the second and third treatment course. Although
switchers had poorer treatment response and shorter drug sur-
vival than non-switchers, approximately half of switchers
achieved clinical response. Two years after switching, half of
switchers maintained treatment with the second biological.
Lack of efcacy explained half of the switch episodes, fol-
lowed by AE in one out of four. Switches were almost exclu-
sively between TNFi. Previous observational studies have
included a limited number of switch-episodes. Lie et al found
switching in 77/514 (15%) AS patients during 9 years of
follow-up mainly due to AE.22 A French study described
switching in 99/377 (26%) patients with spondyloarthropaties
during 8 years of follow-up, the main reason was LOE.20 These
differences are unexplained but possibly reect regional differ-
ences in prescription practice.
We found that switchers were more often women and had
higher subjective disease activity compared with non-switchers
when starting the rst TNFi, CRP and BASMI were similar.
The Norwegian study found no such differences,22 however,
the study may have been underpowered as baseline data only
was available in 39% of switchers. Studies performed in RA
patients report a similar tendency towards higher baseline
disease activity among switchers.5 9 This might reect that
Ann Rheum Dis 2013;72:11491155. doi:10.1136/annrheumdis-2012-201933
 Clinical and epidemiological research

Table 3 CRP level, VAS and BAS scores during the first (n=1436), conservative measure than the BASDAI50%/20 mm response
second (n=432) and third treatment course (n=137) used in the current study. However, in spite of great variation in
Treatment duration p p
study design and methodology, previous studies overall describe
Treatment 0 vs 3 0 vs 6
high response rates among AS patients switching therapy.
course 0 months 3 months 6 months months months Increased CRP and low BASFI were associated with treatment
response during the second treatment course. A similar pattern
CRP (mg/l) has previously been described among AS patients receiving their
1 13 (5.026) 4.0 (1.09.0) 4.0 (1.09.0) 0.001 0.001 rst TNFi.24 3136 However, one previous study among 99
2 8.0 (2.020) 5.0 (2.011) 3.0 (1.07.0) 0.09 0.001 patients with spondyloarthropaties switching TNFi found no
3 9.0 (3.021) 4.0 (1.012) 6.0 (2.011) 0.2 0.1 predictors,20 perhaps due to lack of power. Perhaps increased
VAS fatigue (mm) levels of CRP identify patients with higher cytokine mediated
1 68 (5081) 33 (1660) 32 (1261) 0.001 0.001 inammation and therefore better response to TNFi. On the
2 68 (4782) 49 (1774) 41 (1769) 0.001 0.001 contrary, higher BASFI might be associated with chronic disabil-
3 71 (6082) 61 (3984) 54 (3178) 0.02 0.04 ity or psychological factors irresponsive to treatment.31
VAS global (mm) Currently, inammatory markers and functional status are not
1 68 (4981) 25 (1151) 24 (1052) 0.001 0.001 included in the guidelines for prescribing TNFi in AS. However,
2 68 (4581) 38 (1267) 36 (1565) 0.001 0.001 possible predictors must be interpreted with caution in clinical
3 71 (5685) 60 (4676) 57 (3076) 0.04 0.01 settings: we found increased CRP to predict clinical response
VAS pain (mm) after switching and 50% of patients with CRP>10 mg/l achieved
1 65 (4678) 22 (948) 20 (947) 0.001 0.001 a BASDAI 50%/20 mm within 6 months. However, 30% of
2 62 (4078) 36 (1262) 31 (1156) 0.001 0.001 patients with normal CRP also achieved response. More compli-
3 66 (4583) 57 (4074) 48 (2875) 0.06 0.04 cated models are needed in order to predict clinical outcome of
BASDAI (mm) therapy in individual patients.32
1 59 (4571) 28 (1148) 28 (1150) 0.001 0.001 We found longer treatment duration of the second biological drug
2 56 (3873) 36 (1964) 33 (1659) 0.001 0.001 in men compared with women. This is in accordance with previous
3 64 (4879) 51 (3667) 52 (2863) 0.002 0.001 studies, not only in AS but also RA and psoriatic arthritis.24 3641
BASFI (mm) Why clinical response differs according to gender is still unclear.
1 50 (3467) 28 (1148) 28 (1150) 0.001 0.001 The main switch patterns were from iniximab to adalimu-
2 52 (3570) 36 (1760) 41 (1758) 0.001 0.001 mab or etanercept. This reects that iniximab was the rst
3 64 (4279) 51 (3073) 52 (3874) 0.02 0.04 TNFi marketed to treat AS. Among patients starting treatment
BASMI in year 2008 and thereafter, the most prevalent switch was
1 40 (2060) 20 (1050) 30 (1050) 0.001 0.001 from adalimumab to etanercept (48/157 switches). Drug sur-
2 30 (2050) 30 (1040) 30 (1050) 0.08 0.007 vival during the second treatment course was longer among
3 40 (2060) 35 (2050) 40 (2050) 0.03 0.006 adalimumab treated patients and among patients previously
Results from Wilcoxon signed rank test. Values are medians and IQR. treated with iniximab. However, we found no difference in
Outcome data were reported according to the registrations in DANBIO at the efcacy among the different TNFi. Due to the non-randomised
following time-points: 0 months (upon initiation of therapy), 3 months
(1017 weeks), 6 months (1832 weeks). If more registrations occurred within a
study design, these results must be interpreted with caution.
given time interval, the one closest to the given time-point was selected. If a Comorbidity, route of drug administration (subcutaneous/intra-
patient had no registrations within a given time interval, data were registered as venously) and altered clinical practice due to marketing of new
missing for the given time-point. drugs might have affected the results.13 38
BASDAI, Bath AS Disease Activity Index; BASFI, Bath AS Function Index; BASMI, The treatment response of the second biological drug was
Bath AS Metrology Index; CRP, C reactive protein; VAS, visual analogue scale.
similar among switchers due to LOE and AE. Some have
reported similar results17 20 22others describe better treat-
switchers are patients refractory to treatment for example, due ment effects among AE-switchers.8 12 14 Our study was limited
to chronic disability or comorbidities.31 by the fact that it was not possible to distinguish between
In the present study, response rates were markedly reduced treatment termination due to lack of or loss of treatment
among switchers. Similar results were found by Lie et al22 effect. According to some studies, patients who stop treatment
Rudwaleit et al reported response among 41% of 326 adalimu- due to secondary loss of treatment effect especially benet
mab treated patients with AS who previously failed treatment from switching.12 14 Smoking status, comorbid disease, con-
with iniximab and/or etanercept compared with 63% among comitant use of NSAIDs, enthesitis and HLAB27 status are
TNFi-nave patients ( p<0.001).14 Furthermore, we found factors that might inuence treatment outcome.32 However
decreased drug survival after switching. Similar tendencies have these data are not routinely registered in DANBIO.
previously been demonstrated.9 13 14 22 In conclusion, nearly one-third of AS patients switched
Although the response rates and drug survivals decreased TNFi in routine care during up to 10 years of follow-up, mainly
after switching, the 6 months response rate was 37% during due to inefcacy. The response rates and drug adherences
the second treatment course. After 2 years of treatment, 52% decreased after switching. However, half of the switchers
of switchers had achieved BASDAI50/20 mm response and achieved clinical response. Thus, irrespective of the reason for
54% a BASDAI <40 mm. Rudwaleit et al and Lie et al reported discontinuation of the rst TNFi, switching to another TNFi
BASDAI50 response among 41%14 and 28% of switchers.22 should be considered.
Observational studies including <25 patients report 4383%
response rates.8 1518 A retrospective study among 56 switchers Author afliations
1
Department of Rheumatology, Gentofte University Hospital, Copenhagen, Denmark
found a 80% response rate after 3 months treatment.20 It 2
The Danish Rheumatologic Database (DANBIO), Glostrup, Denmark
should be noted that several clinical studies measure response 3
Department of Rheumatology, Copenhagen University Hospital Glostrup, Glostrup,
rates as 50% reductions in BASDAI,14 17 22 which is a more Denmark

Ann Rheum Dis 2013;72:11491155. doi:10.1136/annrheumdis-2012-201933 1153

 Clinical and epidemiological research
Figure 3 Disease activity for switchers at baseline, 3 months and 6 months during biological treatment course 1 (red). course 2 (grey) and course
3 (green) (n=432). Columns show medians. Panel A: C reactive protein (CRP), panel B: Bath AS Activity Index (BASDAI), panel C: Visual analogue
scale (VAS) global. This gure is only reproduced in colour in the online version.
4
Zitelab Aps, Copenhagen, Denmark
5
Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
6
Department of Rheumatology, Frederiksberg Hospital, Copenhagen, Denmark
7
Department of Rheumatology, Vejle Sygehus, Sygehus Lilleblt, Vejle, Denmark
8
Department of Rheumatology, Aalborg Hospital, Aalborg, Denmark
9
Department of Rheumatology, Kge Hospital, Kge, Denmark
10
Department of Rheumatology, Odense University Hospital, Odense, Denmark
11
Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen,
Denmark
12
Department of Rheumatology, Vendsyssel Hospital, Hjrring, Denmark
13
Department of Rheumatology, Esbjerg Hospital, Esbjerg, Denmark
14
Department of Rheumatology, Helsingr Hospital, Helsingr, Denmark
15
Department of Rheumatology, Regionshospital Randers, Randers, Denmark
Acknowledgements Thanks to the departments of rheumatology in Aalborg,
Aarhus, Esbjerg, Fredericia, Frederiksberg, Gentofte, Glostrup, Grsten, Hjrring,
Holbk, Holstebro, Horsens, Helsingr, Kolding, Kge, Nstved/Nykbing Falster,
Odense, Randers, Rigshospitalet, Roskilde, Silkeborg, Slagelse, Svendborg, Vejle,
Viborg, Denmark for reporting to the DANBIO registry.
Contributors All coauthors fullled criteria for co-authorship according to the
Vancouver Protocol.
Competing interests M: Abbott, Centocor, GSK, MSD, Mundipharma, Novo, Pzer,
Roche, UCB, Wyeth (less than 10.000 USD each); AGL: MSD, UCB, Abbott (less than
10.000 USD each); AS: MSD, Pzer, Roche (less than 10.000 USD each); HML: Roche,
MSD (less than 10.000 USD each); CR: Pzer, Abbott (less than 10.000 USD each);
MLH: Abbott, Centocor, Roche, Pzer (less than 10.000 USD each); BG, NSK, UT, NM,
AH, VF, HN, LE, DVJ and PMP declare no conict of interest.
Ethics approval The study reports data from a National Registry. Thus, approval
from the regional ethics committee is not required. This is also stated in the
methods section of the paper.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it was published online
rst. Figure 2 has been altered.
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