Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

I.Y.K. Iskandar1, D. M. Ashcroft1, R.B. Warren2, I.Evans2, K. McElhone2, C.M. Owen3, A.D. Burden4, C.H. Smith5, N.J. Reynolds6, and C.E.M. Griffiths2

1Centre for Pharmacoepidemiology and Drug Safety, Manchester Pharmacy School, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.2Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.3 Department of Dermatology, East Lancashire Hospitals NHS Trust, RoyalBlackburnHospital, Blackburn, UK.4Department of Dermatology, Western Infirmary, Glasgow, UK.5St. John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.6 Dermatological Sciences, Institute of Cellular Medicine, Medical School, Newcastle University, and Department of Dermatology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Correspondence

Miss Ireny Y. K. Iskandar

Centre for Pharmacoepidemiology and Drug Safety,

Manchester Pharmacy School, The University of Manchester,

Room 1.134, 1st Floor, StopfordBuilding

Oxford Road, Manchester, M13 9PT, UK.

Email: ireny.iskandar@manchester.ac.uk

Page number: 21 Pages

Manuscript word, table and figure count: 3090 words,4 Tables and 3 Figures

Running heading:

Utilisation & dosing patterns of biologic therapies in the management of psoriasis

Funding:

The British Association of Dermatologists Biologic Interventions Register (BADBIR) is

coordinated by the University of Manchester. BADBIR is funded by the British Association of

Dermatologists (BAD). The BAD receives income from Pfizer, Janssen Cilag, Abbvie,

Novartis and Samsung Bioepis for providing pharmacovigilance services. This income

finances a separate contract between the BAD and the University of Manchester who

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coordinate BADBIR. All decisions concerning analysis, interpretation, and publication are

made independently of any industrial contribution.

Conflicts of Interest:

D.M. Ashcroft has received grant funding from Abbvie and served on advisory boards for

Pfizer and GSK. R.B. Warren has acted as a consultant and/or speaker and/or received

research grants for Abbvie, Amgen, Celgene, Eli Lilly, Pfizer, Novartis, and Janssen, all of

whom manufacture biologic therapies. A.D. Burden has acted as lecturer, consultant, and

researcher for Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Novartis,

and Pfizer. C.H. Smith's department has received funding for research support from AbbVie,

Janssen, Novartis, Wyeth and Pfizer. N.J. Reynolds has received honoraria, travel support,

consulting income, and/or research grants (Newcastle University) from Abbvie, Amgen,

AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Leo-Pharma Research

Foundation, Novartis, Pfizer, and Stiefel GSK. C.E.M. Griffiths has received honoraria and/or

research grants from Abbvie, Actelion, Amgen, Celgene, LEO Pharma, Eli Lilly, GSK-Stiefel,

Janssen, MSD, Novartis, Pfizer, Sandoz and UCB Pharma.

What's already known about this topic? Published evidence concerning the

utilisation patterns of biologic therapies for psoriasis, including dosing, switching,

discontinuation and restarts is limited to biologic-naïve patients. Furthermore, the

ability to determine the patterns of concomitant use of conventional systemic

therapies with biologic therapies is confined to a few small-scale studies.

What does this study add? Based on a cohort of 2980 patients receiving biologic therapies for psoriasis,

33.7% of patients experienced treatment modifications during the first year of

treatment.

There were no significant differences between biologic-naïve and non-naïve

patients in the proportion who switched, discontinued or restarted therapy.

Conventional systemic therapies, particularly methotrexate, are commonly used

concurrently with biologics.

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Abstract

Background: Treatment modifications, including dose-escalations, dose-reductions,

switches, discontinuations and restarts of biologics may be necessary in the management of

psoriasis but the patterns of usage are incompletely defined.

Objectives: To examine the treatment utilisation patterns of adalimumab, etanercept and

ustekinumab among biologic-naïve and non-naïve psoriasis patients enrolled in the British

Association of Dermatologists Biologic Interventions Register (BADBIR).

Method: The cohort study included adults with chronic plaque psoriasis who were followed-

up for ≥12-months.Treatment modifications were assessed during the first year of therapy.

The time-trend method, comparing the cumulative dose (CD) patients received to the

recommended cumulative dose (RCD), was used to assess dosing patterns. Concomitant

use of other systemic treatments was also examined.

Results: In total, 2980 patients (adalimumab:1675; etanercept:996; ustekinumab:309) were

included; 79.2% were biologic-naïve. Over 12-months, 77.4% of patients continued the

biologic, 2.6% restarted therapy after a break of ≥90-days, 2.5% discontinued, and 17.5%

switched biologic therapy. Most patients (85.7%) received the RCD of the biologic, although

8.1% were exposed to a higher CD. In total, 749(25.1%) patients used conventional

systemic therapies concomitantly with a biologic at some stage; methotrexate was used

most commonly (458;61.2%). Of those using combination therapy, 454(60.6%) continued the

use of the conventional systemic therapy for >120 days after the start of the biologic.

Conclusion: More than one-third of patients experienced treatment modifications within the

first year of initiating a biologic. Conventional systemic therapies, particularly methotrexate,

were commonly used concurrently which should be considered when evaluating treatment

response and adverse events to biologics in real-world observational studies.

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IntroductionBiologic therapies have revolutionised the treatment of moderate-to-severe psoriasis. Those

currently licensed for psoriasis include the tumour necrosis factor inhibitors: adalimumab,

etanercept and infliximab; interleukin (IL)-17A inhibitors: secukinumab and ixekizumab; and

IL-12/23 inhibitor, ustekinumab.

Although the licensed dosing-regimens of biologics are established in large randomised

controlled trials, clinical-practice suggests that alternative dosing-regimens may be

necessary. These can be broadly categorised into dose-escalation, dose-reduction, and

interrupted-therapy1. The reasons for these adjustments may include attempts to improve

effectiveness, including: dose-escalation in obese patients for whom standard dosing-

regimens are ineffective; to address increasing dose-tolerance over-time (including the

development of anti-drug antibodies); gaps in treatment schedules to prepare for surgery

with significant risk of infection or; following the development of adverse-events1. A

systematic review by Brezinski et al.1 identified 23 prospective clinical-trials2-12, that

evaluated changes in dosing-regimens of biologics for psoriasis patients who were non-

responders. Among non-responders, dose-escalation with adalimumab, etanercept, and

ustekinumab usually resulted in greater efficacy than standard dosing-regimens1. However

the utilisation profile of biologics cannot be adequately assessed in clinical-trials as these are

restricted by their inclusion criteria and size, resulting in low external validity for "real-world"

psoriasis populations13.

Several studies have reported on the utilisation patterns of biologics for psoriasis based on

employer-based claims databases. These studies employed different methods, resulting in a

range of estimates14-21. For instance, Wu et al.20 reported that 33-50% of patients required

dose-escalation during their first-year of etanercept therapy, while Thayer et al.14 reported

that etanercept usage over one-year of follow-up was stable and patients used 98-104% of

the US label-recommended doses. The diverse estimates reported from these studies are

likely to be due to the different measures employed, highlighting a lack of consensus on an

optimal method to evaluate dosing patterns22. Several small-scale studies have also reported

on the utilisation of biologics in UK clinical-practice23-26. Nevertheless, the generalisability of

their findings may be limited by small sample size ranging from 46-169 patients.

Information on dosing patterns has important economic implications27. In addition, changes

in dosing-regimen may affect clinical-effectiveness and likelihood of adverse events. For

instance, a recent systematic review examining the risk of serious infection during biologic

treatment of patients with rheumatoid arthritis has suggested that "high-dose" use of

biologics was associated with an increased risk of serious infection28.

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Published evidence on the utilisation patterns of biologics for psoriasis is based mainly on

biologic-naïve patients, little is known about the utilisation patterns among biologic

experienced patients. Furthermore, the addition of conventional systemic therapies used to

treat psoriasis after or at the initiation of biologics has only been studied in three, small-scale

studies24-26, thereby limiting the ability to determine their pattern of use. Large-scale cohorts

are required to fully understand these utilisation-patterns.

The British Association of Dermatologists Biologic Interventions Register (BADBIR) is a

pharmacovigilance register which represents a valuable resource to assess real-world

utilisation patterns of biologics for psoriasis due to its size, and high external validity with

over 150 participating dermatology centres29. The aim of this study was to examine the

utilisation and dosing patterns of adalimumab, etanercept and ustekinumab within the first

12-months of treatment among biologic-naïve and non-naïve psoriasis patients. Concomitant

therapy with other systemic treatments was also examined.

Methods

The BADBIR, established in September 2007, compares a cohort of psoriasis patients on

biologics to a similar cohort on conventional systemic therapies. Details about the design of

BADBIR and the disease characteristics of its participants has been published previously29,30.

BADBIR was approved by the NHS Research Ethics Committee North West England in

March 2007(reference 07/MRE08/9) and all subjects gave their written consent for

participation. Subjects in this study were selected from the August 2014 data-cut.

Baseline assessment

Data collected at enrolment included patients' demographic characteristics and co-

morbidities; details of type and severity of psoriasis defined by Psoriasis Area Severity Index

(PASI), and year of onset; standardised measures of health status using self-reported

outcome measures (Dermatology Life Quality Index(DLQI)); and detailed information about

the patients' current and previous treatment for psoriasis. Co-morbidities were classified

using the Medical Dictionary for Regulatory Activities (MedDRA) system31.

Follow-up assessments

Data from patients were collected at 6-month intervals during the study period. Details of

biologics, including any change in dose or biologic therapy, start and stop dates, and reason

for discontinuation were recorded. For adalimumab and etanercept the dosing-regimen was

recorded, whereas for ustekinumab, the dose and date of administration was documented.

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Information on any new concomitant conventional systemic therapies and their start and stop

dates was also captured.

Patient selection

Adult patients with chronic plaque psoriasis, receiving adalimumab, etanercept or

ustekinumab were included if they had been followed up for ≥12-months and had complete

records of dosing information. The study time-frame was from September 2007-August

2014; the patients had to be enrolled into BADBIR before August 2013 to allow at least 12-

months of follow-up for all patients. The index-date (the start of observation time) was

defined as the startdate of the index-biologic (therapy received at enrolment). Patients were

classified as either biologic-naïve or non-naïve based on their previous exposure to biologics

prior to enrolment into BADBIR. Due to the stricter eligibility criteria for use of infliximab in

most of the UK32, the proportion of patients managed by infliximab who fulfilled the inclusion

criteria was very low (90 patients), thus infliximab patients were excluded.

Outcome measures

The primary outcomes for the analysis were changes in medication utilisation (dose-

escalation/reduction, switching, discontinuation and restarting therapy) which were evaluated

in the first 12-months of follow-up. Patterns of use of conventional systemic therapies

concomitantly with a biologic were also examined.

Continuous use of biologic therapy was defined as not having any gaps in treatment that

exceeded a 90-day period. This permissible treatment gap of 90-days was used to disregard

temporary treatment discontinuation due to clinical reasons, and to take into account the

early UK licensing of etanercept as an intermittent dosing-regimen with gaps of <90 days33.

Patients with a gap of ≥90-days after the index-date were defined as discontinuing their

index-biologic and were further classified into one of the three mutually exclusive groups

based on the treatment patterns after the first 90-day gap: discontinued, restarted, or

switched therapy. Patients were classified as discontinued therapy if they did not receive

any biologic after the first 90-day gap; patients were classified as restarted if they had a

treatment gap that exceeded the 90-day period and subsequently re-started the same

biologic therapy; patients were classified as switched therapy if they initiated a new biologic

after the first 90-day gap. As the switching patterns could be affected by the introduction of

new biologic therapies (such as, ustekinumab) or the withdrawal of others (such as,

efalizumab), switchers were stratified over time periods (2008-2009, 2010-2012 and 2013-

2014) based on the year they switched therapy.

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Dosing for each biologic was calculated as the average weekly dose; for adalimumab and

etanercept, the average weekly dose was a function of the dose and dosing interval based

on the recorded dosing-regimen; whereas for ustekinumab the average weekly dose was a

function of the dose and the intervals between the administered doses, which were

calculated in number of weeks. Interval patterns for ustekinumab were assessed based on a

window around the recommended dosing interval (4±1 weeks for the interval of index to

second dose, and 12±1 weeks for the interval of second, third dose and subsequent doses).

The time-trend method, which compares the annual cumulative dose (CD) patients received

to the annual recommended cumulative dose (RCD) per product prescribing information,

was used to assess dosing patterns34. The CD that a patient received over the first-year of

therapy was calculated as a time-varying variable taking into consideration any gaps in

treatment of <90-days. The annual CD was then compared to the annual RCD. The annual

RCDs according to NICE guidelines32 were: 2600mg (50mgx52 weeks) for etanercept;

1120mg (80mg+(40mgx26 weeks)) for adalimumab and; 270mg (45mgx6 doses), or 540mg

(90mgx6 doses) if >100Kg, for ustekinumab.

Bridging therapy was defined as conventional systemic therapy started before or at the time

of biologic initiation and used concomitantly with the biologic for ≤120-days, whereas rescue

therapy was defined as additional conventional systemic therapy started after the first 120-

days of biologic therapy (Fig.1). The 120-day threshold was chosen based on clinical expert

opinion and biologic therapy guidelines which state that therapy with adalimumab,

etanercept or ustekinumab can be continued beyond 12-16 weeks only in those patients who

respond according to criteria determined by NICE32.

Data analysis

Patients were assigned to one of three unique biologic cohorts based on their index-biologic

and recorded as either biologic-naïve or non-naïve. Patient demographics and disease

characteristics upon enrolment were analysed. Descriptive analysis was used to summarise

the data (mean±SD or frequencies) as appropriate. Differences between biologic cohorts

and between naïve and non-naïve patients within each cohort were tested using analysis of

variance (ANOVA) and t-tests, respectively, or their non-parametric equivalents Kruskall-

Wallis and Mann-Whitney U tests for continuous data and chi-square tests for categorical

data. Chi-square tests were also used to assess between-cohorts and within-cohort

differences for dose-escalation/reduction, restart, switching and discontinuation. Given the

large cohort studied and multiple tests, p≤0.01 was considered to be statistically significant.

All statistical analyses were conducted using Stata v.13 (Stata Corp, College Station, TX).

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Results

Overall, 2980 patients met the study criteria, including 1675 (56.2%) on adalimumab; 996

(33.4%) on etanercept and 309 (10.4%) on ustekinumab (Fig.2). The mean (±SD) age of

patients, and disease duration were 45.9 (12.5) years, and 22.9 (12.3) years, respectively,

with 60.9% male. Mean PASI and DLQI scores at enrolment were 16.4±7.8 and 17.1±7.5,

respectively, with 12.4% suffering from unstable psoriasis. The mean (±SD) body mass

index (BMI) was 31.0±7.2kg/m2, with 46% having a BMI >30kg/m2. In total, 75.9% of patients

had one or more co-morbidities. Baseline demographic and disease characteristics are

summarised in Table 1.

Utilisation patterns

Over the 12-month follow-up period 77.4% of patients continuously used their index-biologic

and had no gaps in therapy of ≥90-day (Fig.3), with no significant difference in the proportion

of patients who continuously used their index-biologic between naïve and non-naïve patients

within each biologic cohort. Fourteen percent of patients discontinued treatment due to lack

of effectiveness; 4.6% as a result of adverse events; and 4.1% for other reasons.

In total, 673 (22.6%) patients had ≥90-day gap in therapy. Of these patients, 521 (77.4%)

patients switched to an alternative biologic therapy, 78 (11.6%) patients restarted therapy

after a break of ≥90-day, and 74 (11.0%) patients discontinued therapy. Specifically, 239

(14.3%), 234 (23.5%) and 48 (15.5%) of adalimumab, etanercept and ustekinumab patients,

respectively, switched therapy (p<0.001); 55 (3.3%), 17 (1.7%) and 6 (1.9%) of adalimumab,

etanercept and ustekinumab patients, respectively, restarted therapy (p=0.001); and 46

(2.7%), 16 (1.6%) and 12 (3.9%) of adalimumab, etanercept and ustekinumab patients,

respectively, discontinued therapy (p=0.002; Fig. 3). There was no significant difference in

the proportion of patients who switched, restarted or discontinued therapy between naïve

and non-naïve patients within each biologic cohort. Treatment switching patterns amongst

those that switched therapy are summarised in Table 2.

Dosing patterns

Overall, 85.7% of patients received the RCD of the biologic therapy, with 6.2% of patients

being exposed to a lower CD and 8.1% of patients being exposed to a higher CD (Table 3).

Specifically, 2.5%, 5.2% and 30.0% of adalimumab, etanercept and ustekinumab patients,

respectively, were exposed to a lower CD; while 4.5%, 11.4% and 17.7%, respectively, were

exposed to a higher CD (p<0.001; Table 3). A significant difference in the dosing pattern

between etanercept naïve and non-naïve patients was identified (Table 3), with a higher

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proportion of naïve patients being exposed to the RCD. In contrast, there was no significant

difference in the dosing pattern between naïve and non-naïve adalimumab and ustekinumab

patients. In all but one case, higher rates for changes in utilisation of ustekinumab were due

to differences with administration intervals rather than prescribed dose.

Interestingly, patients exposed to a higher CD had a higher mean BMI at baseline compared

to patients exposed to a lower CD or those receiving the RCD (32.0±7.0 Kg/m2, 30.6±6.5

Kg/m2 and 30.6±6.9 Kg/m2, respectively, p=0.038).Patients receiving a higher cumulative

dose also had a higher mean body weight at baseline compared to patients exposed to a

lower cumulative dose or those receiving the recommended cumulative dose (94.0±21.1Kg,

88.8±20.6 Kg, and 89.9±20.7 kg, respectively, p=0.029).Furthermore, those exposed to a

higher CD were more likely to have unstable psoriasis at baseline compared to those

receiving a lower CD or the RCD (18.8%, 13.2% and 10.8%, respectively, p=0.019).

Pattern of use of conventional systemic therapiesconcomitantly with biologics

In total, 749 (25.1%) patients used conventional systemic therapies concomitantly with a

biologic. Specifically, 427 (25.5%), 252 (25.3%) and 70 (22.7%) of adalimumab, etanercept

and ustekinumab patients, respectively, used conventional systemic therapies concomitantly

with a biologic (p=0.556). The most commonly prescribed concomitant therapies were

methotrexate (458;61.2%) and ciclosporin (219;29.2%). However, acitretin (72;9.6%),

fumaric acid esters (37;4.9%) and hydroxycarbamide (15;2.0%) were also co-prescribed.

Fifty-two patients (1.7%) were treated with different conventional systemic therapies at

different times e.g. ciclosporin as a bridging therapy and methotrexate added later as a

rescue therapy (Table 4).

Of those patients receiving combination therapy, 454(60.6%) continued the use of the

conventional systemic therapy for >120-days after the start of biologic therapy, whereas 160

(21.4%) and 152 (20.3%) used the conventional systemic therapy as bridging or rescue

therapy, respectively. Among patients who used the conventional systemic therapy either for

>120-days or as rescue therapy, methotrexate was used most commonly, whereas

ciclosporin was most frequently used as bridging therapy (Table 4). Interestingly, of those

patients receiving combination therapy, 227 (30.3%) patients had psoriatic arthritis.There

was no difference in the proportion of patients using concomitant conventional systemic

therapies between those exposed to higher CD, lower CD or the RCD.

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Discussion

In this cohort study examining the real-world utilisation and dosing patterns of adalimumab,

etanercept and ustekinumab, over one-third of patients experienced some form of treatment

modification during the first 12-months' treatment. Biologic naïve and non-naïve patients

showed no significant differences in the proportion who switched, restarted or discontinued

therapy. One of the most notable findings was that conventional systemic therapies

particularly methotrexate, were commonly used concurrently with biologics, with 15% of

patients continuing their use for >120-days after start of the biologic.

To our knowledge, this is the first study that has reported on the utilisation and dosing

patternof biologics among biologic-naïve and non-naïve psoriasis patients. Our findings differ

from earlier reports of etanercept and adalimumab treatment patterns in US health-plans in

which a higher proportion of patients who had gaps in therapy either discontinued or

restarted their index-biologic; and only 6-20% of patients switched to another biologic16,17,19,21.

Whereas, we found that 70-88% of patients who had a ≥90-day gap in therapy switched to

an alternative biologic.

Using the time-trend method, which provides the most comprehensive information on dosing

patterns in clinical-practice34, we robustly assessed the dosing pattern of adalimumab,

etanercept, and ustekinumab over time. The time-trend method has the advantage of

examining dose-escalation/reduction relative to the RCD, taking into account the cumulative

period of exposure to the drug. Other studies14,15,20 have used different analytical methods

that are associated with limitations in determining exposure to treatments, which may lead to

different interpretations of the usage patterns of biologics. For instance, Wu et al.20 defined

the absence of dose-decrease as a dose-increase; while Feldman et al.15 used a threshold

of 25% to define a significant dose-increase (or decrease) to which the rates of dose-

escalation/reduction may be sensitive with fewer patients experiencing

dose-escalation/reduction with higher thresholds. This approach is often used when the

objective is to evaluate dose-escalation/reduction beyond a certain threshold34, but can fail to

distinguish between multiple changes over time and therefore may only account partially for

dose-escalation/reduction34.

The results of our study demonstrate that the majority of psoriasis patients in the UK receive

the RCD of biologic therapy. The low proportion of patients with a CD higher than the RCD is

likely to be related to the system of public funding for biologic therapies in the UK, where

applications for up-titration are often not accepted33. Interestingly, a significantly lower

proportion of ustekinumab patients were exposed to the RCD compared to adalimumab or

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etanercept patients. This may be due in part to the relatively wide dosing schedule of

ustekinumab, hence a delay in the administration of one dose would increase the intervals

between doses and ultimately the patient would be exposed to a CD less than the RCD.

Another study of 374 psoriasis patients who were initiated on ustekinumab reported that of

those who received their third ustekinumab dose, 75.9% had their third dose administered as

expected, while the rest had their dose administered earlier (8.7%) or later (15.4%) than

expected35. The rates of patients receiving their third dose later than expected is slightly

lower than that observed in our analysis because of the use of a wider window around the

recommended dosing intervals.

The major strengths of our study are the prospective real-world cohort study design and

detailed data capture allowing the analysis of information that may affect study outcomes,

such as concurrent conventional systemic therapies. Additionally, the large sample size and

the broad inclusion criteria ensure high external validity. As BADBIR was established

primarily as a pharmacovigilance register, limitations to studying medication utilisation

patterns are inherent to the study design such as information on patients’ adherence to

treatment and the intention behind use of concomitant conventional systemic therapies. An

inherent limitation to an observational study is non-randomisation, which, in turn, may

introduce selection bias.

Although biologic treatment for psoriasis has been associated with reduced frequency of

medical service utilisation and reduced health-care costs36, this study highlights the frequent

use of conventional systemic therapies concomitantly with biologics in routine clinical-

practice hence further studies are needed to assess the impact of dosage-increase and the

concomitant use of conventional systemic therapies on total health-care costs. Moreover,

studies assessing whether dosage-increases are associated with improved effectiveness are

warranted, because of the potential to also increase the risk of adverse drug events. We

investigated utilisation and dosing patterns of biologics during the first-year of treatment only,

future studies with more than one-year of follow-up are needed, particularly to describe

whether patients who experienced treatment modification during the first-year are more or

less likely to experience any other treatment modifications in subsequent years.

In summary, we have shown that treatment modifications were common in the first-year of

treatment, affecting approximately one-third of psoriasis patients receiving adalimumab,

etanercept or ustekinumab. Concomitant use of conventional systemic therapies, particularly

methotrexate, was frequent and should be considered when evaluating treatment response

and adverse events to biologic therapies in real-world cohort studies.

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19 Bonafede M, Fox KM, Watson C et al. Treatment patterns in the first year after initiating tumor necrosis factor blockers in real-world settings. Adv Ther 2012; 29: 664-74.

20 Wu EQ, Feldman SR, Chen L et al. Utilization pattern of etanercept and its cost implications in moderate to severe psoriasis in a managed care population. Curr. Med. Res. Opin. 2008; 24: 3493-501.

21 Doshi JA, Takeshita J, Pinto L et al. Biologic therapy adherence, discontinuation, switching, and restarting among patients with psoriasis in the US Medicare population. Journal of American Academy of Dermatology 2016: 1-9.

22 Ariza-Ariza R. , Navarro-Sarabia F. , Herna´ndez-Cruz B. et al. Dose escalation of the anti-TNF-α agents in patients with rheumatoid arthritis. A systematic review. Rheumatology (Oxford). 2007; 46: 529-32.

23 Khalid JM, Fox KM, Globe G et al. Treatment patterns and therapy effectiveness in psoriasis patients initiating biologic therapy in England. Journal of Dermatological Treatment 2014; 25: 67-72.

24 Warren RB, Brown BC, Lavery D et al. Biologic therapies for psoriasis: practical experience in a U.K. tertiary referral centre. Br J Dermatol 2009; 160: 162-9.

25 Warren RB, Brown BC, Lavery D et al. Adalimumab for psoriasis: practical experience in a U.K. tertiary referral centre. Br J Dermatol 2010; 163: 859-62.

26 Laws PM, Downs AM, Parslew R et al. Practical experience of ustekinumab in the treatment of psoriasis: experience from a multicentre, retrospective case cohort study across the U.K. and Ireland. Br J Dermatol 2012; 166: 189-95.

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27 Joint Formulary Committee. British national formulary (BNF), 70th edn. London: British Medical Association and The Royal Pharmaceutical Society of Great Britain. 2015.

28 Singh JA, Cameron C, Noorbaloochi S et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet 2015; 386: 258-65.

29 Burden AD, Warren RB, Kleyn CE et al. The British Association of Dermatologists' Biologic Interventions Register (BADBIR): design, methodology and objectives. Br. J. Dermatol. 2012; 166: 545-54.

30 Iskandar IYK, Ashcroft DM, Warren RB et al. Demographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register. Br. J. Dermatol. 2015; 173: 510-8.

31 Bousquet C, Lagier G, Lillo-Le Louet A et al. Appraisal of the MedDRA conceptual structure for describing and grouping adverse drug reactions. Drug Saf. 2005; 28: 19-34.

32 National Institute for Health and Care Excellence. Psoriasis: the assessment and management of psoriasis. Clinical Guideline 153. In: London: National Institute for Health and Care Excellence. 2012; WWW document.

33 Warren RB, Smith CH, Yiu ZZ et al. Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J. Invest. Dermatol. 2015; 135: 2632–40.

34 Huang X, Gu NY, Fox KM et al. Comparison of methods for measuring dose escalation of the subcutaneous TNF antagonists for rheumatoid arthritis patients treated in routine clinical practice. Curr. Med. Res. Opin. 2010; 26: 1637-45.

35 Cai Q, Carter C, AbuDagga A et al. Real-world dosing and utilization of ustekinumab among patients with psoriasis. . The American Journal of Pharmacy Benefits 2014; 6: 129-36.

36 Bhoslea MJ, Feldmanb SR, Camachob FT et al. Medication adherence and health care costs associated with biologics in Medicaid-enrolled patients with psoriasis. Journal of Dermatological Treatment 2006; 17: 294–301.

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Figure Legends

Figure 1: Patterns of use of conventional systemic therapies concomitantly with biologic

therapies.

Figure 2: Patient selection.

Figure 3: Rates of continuous use, restart, switching & discontinuation of biologic therapy

over the first 12-months of therapy.

Acknowledgement

The authors acknowledge the substantial contribution of the BADBIR team to the

administration of the project in particular the database manager Mr Hassan Ali, for his advice

and support. BADBIR acknowledges the support of the National Institute for Health

Research (NIHR) through the clinical research networks and its contribution in facilitating

recruitment into the registry. The views and opinions expressed therein are those of the

authors and do not necessarily reflect those of the BADBIR, NIHR, NHS or the Department

of Health.

The authors are grateful to the members of the Data Monitoring Committee (DMC): Dr

Robert Chalmers, Dr Carsten Flohr (Chair), Dr Karen Watson and David Prieto-Merino and

the BADBIR Steering Committee (in alphabetical order): Prof Jonathan Barker, Ms Marilyn

Benham (CEO of BAD), Prof David Burden(Chair), Mr Ian Evans, Prof Christopher Griffiths,

Dr Sagair Hussain, Dr Brian Kirby, Ms Linda Lawson, Dr Kayleigh Mason, Dr Kathleen

McElhone, Dr Ruth Murphy, Prof Anthony Ormerod, Dr Caroline Owen, Prof Nick Reynolds,

Prof Catherine Smith and Dr Richard Warren.

Prof. Nick J. Reynolds’s research is supported by the National Institute for Health Research

(NIHR) through Newcastle’s Biomedical Research Centre. Prof. Christopher E.M. Griffiths is

a NIHR Senior Investigator.

Finally, we acknowledge the enthusiastic collaboration of all of the dermatologists and

specialist nurses in the U.K. and the Republic of Ireland who provide the BADBIR data. The

principal investigators at the participating sites are listed at the following website:

http://www.badbir.org

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Table 1: The baseline demographics and disease characteristics of the study cohortCharacterist

icAll study cohort

(n=2980)

Biologic Naïve(2359; 79.2%)

Biologic Non-Naïve(621; 20.8%)

All Naïve patients

Etanercept (911;38.6%

)

Adalimumab

(1291;54.7%)

Ustekinumab

(157;6.7%)

All Non-Naïve

patients

Etanercept (85;13.7%)

Adalimumab (384;61.8%)

Ustekinumab

(152;24.5%)

Demographic (mean, SD for continuous variables; n,% cohort for categorical variables)

Age (years) 45.9(12.5) 45.4(12.6) 45.8(12.8) 45.0(12.3) 46.5(13.0) 47.6(12.0) 46.1(12.5) 48.0(11.8) 47.4(12.4)Male 1814(60.9

%)1446(61.3%)

543(59.6%) 812(62.9%) 91(58.0%) 368(59.3%) 45(52.9%) 226(58.9%) 97(63.8%)

BMI (kg/m2) 31.0(7.2) 30.9(7.3) 30.7(7.2) 31.0(7.2) 31.5(8.0) 31.3(6.9) 31.4(6.9) 31.0(6.8) 31.8(7.0)BMI category (kg/m 2 )

Underweight (<18.5)

25(0.8%) 23(1.0%) 13(1.4%) 8(0.6%) 2(1.3%) 2(0.3%) 0(0.0%) 1(0.3%) 1(0.7%)

Normal (18.5 - 24.99)

480(16.1%) 380(16.1%) 150(16.5%) 199(15.4%) 31(19.8%) 100(16.1%) 16(18.8%) 60(15.6%) 24(15.8%)

Overweight (25 - 29.99)

850(28.5%) 684(29.0%) 260(28.5%) 388(30.1%) 36(22.9%) 166(26.7%) 21(24.7%) 112(29.2%) 33(21.7%)

Obese I (30 - 34.99)

703(23.6%) 556(23.6%) 207(22.7%) 308(23.9%) 41(26.1%) 147(23.7%) 19(22.4%) 90(23.4%) 38(25.0%)

Obese II (35 - 39.99)

405(13.6%) 306(13.0%) 123(13.5%) 166(12.9%) 17(10.8%) 99(15.9%) 14(16.5%) 57(14.8%) 28(18.4%)

Obese III 263(8.8%) 209(8.9%) 72(7.9%) 114(8.8%) 23(14.7%) 54(8.7%) 8(9.4%) 31(8.1%) 15(9.9%)

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(≥40)

Missing 254(8.5%) 201(8.5%) 86(9.4%) 108(8.4%) 7(4.5%) 53(8.5%) 7(8.2%) 33(8.6%) 13(8.6%)

Current Smoker

720(24.2%) 577(24.5%) 206(22.6%) 330(25.6%) 41(26.1%) 143(23.0%) 24(28.2%) 69(18.0%) 50(32.9%)

Psoriatic Arthritis

657(22.1%) 478(20.3%) 177(19.4%) 278(21.5%) 23(14.7%) 179(28.8%) 28(32.9%) 112(29.2%) 39(25.7%)

No comorbidity1

718(24.1%) 619(26.2%) 225(24.7%) 356(27.6%) 38(24.2%) 99(15.9%) 15(17.7%) 56(14.6%) 28(18.4%)

1-2 comorbidities1

1143(38.4%)

901(38.2%) 369(40.5%) 469(36.3%) 63(40.1%) 242(39.0%) 31(36.5%) 158(41.2%) 53(34.9%)

3-4 comorbidities1

727(24.4%) 569(24.1%) 222(24.4%) 312(24.2%) 35(22.3%) 158(25.4%) 22(25.9%) 97(25.3%) 39(25.7%)

≥5 comorbidities1

392(13.2%) 270(11.5%) 95(10.4%) 154(11.9%) 21(13.4%) 122(19.7%) 17(20.0%) 73(19.0%) 32(21.1%)

Disease

Disease Duration (years)

22.9(12.3) 22.3(12.3) 22.4(12.2) 22.2(12.1) 23.1(13.8) 25.2(12.2) 25.7(12.4) 25.6(12.4) 24.1(11.8)

Age of disease onset (years)

22.9(12.7) 23.1(12.7) 23.3(13.3) 22.9(12.2) 23.5(13.1) 22.4(12.9) 20.4(11.5) 22.4(12.9) 23.4(13.5)

PASI 16.4(7.8) 16.9(7.7) 16.6(7.8) 16.9(7.6) 17.9(8.0) 14.5(7.9) 15.7(8.0) 13.4(7.1) 16.2(8.8)DLQI 17.1(7.5) 17.7(7.2) 17.5(7.2) 17.7(7.3) 19.3(6.7) 14.4(7.9) 16.3(7.8) 13.0(7.7) 16.6(7.8)Unstable 368(12.4%) 301(12.8%) 115(12.6%) 162(12.6%) 24(15.3%) 67(10.8%) 10(11.8%) 33(8.6%) 24(15.8%)

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psoriasisAbbreviations: BMI, body mass index; DLQI, dermatology life quality index; PASI, psoriasis area and severity index.1 Co-morbidities were classified according to Medical Dictionary for Regulatory Activities [MedDRA] coding.

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Table 2: Switching pattern among switchers within each biologic cohortYear of switch Started on Etanercept (n = 234) Started on Adalimumab (n = 239) Started on Ustekinumab (n = 48)

Switched to

Adalimumab

(n = 167; 71.4%)

Switched to

Ustekinumab

(n = 45; 19.2%)

Switched to

Infliximab(n = 12; 5.1%)

Switched to

Efalizumab

(n = 10; 4.3%)

Switched to

Etanercept

(n = 38; 15.9%)

Switched to

Infliximab(n = 33; 13.8%)

Switched to

Ustekinumab

(n = 168; 70.3%)

Switched to

Adalimumab (n = 26;

54.2%)

Switched to

Infliximab(n =

17;35.4%)

Switched to

Etanercept (n = 5; 10.4%)

2008 - 2009 36 (21.6%) <5 5 (41.7%)

10 (100.0%) <5 13 (39.4%) <5 <5 0 (0.0%) 0 (0.0%)

2010 - 2012 106 (63.5%) 36 (80.0%) 6 (50.0%) 0 (0.0%) 24 (63.2%) 16 (48.5%) 102 (60.7%) 9 (34.6%) 11 (64.7%) <52013 - 2014 25 (15.0%) 8 (17.8%) <5 0 (0.0%) 10 (26.3%) <5 63 (37.5%) 16 (61.5%) 6 (35.3%) <5

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Table 3: Time-Trend AnalysisEtanercept Adalimumab Ustekinumab p-

value*All (n=729

)

Naïve (n=667

)

Non-Naïve (n=62)

p-value

**

All (n=1335

)

Naïve (n=103

8)

Non-Naïve

(n=297)

p-value

**

All (n=243

)

Naïve (n=12

8)

Non-Naïve (n=11

5)

p-value

**

CD > RCD‡ 83(11.4%)

74(11.1%)

9(14.5%)

0.01

60(4.5%)41(3.9%

)19(6.4%

)

0.04

43(17.7%)

22(17.2%)

21(18.3%)

0.90

<0.001

CD < RCD‡ 38(5.2%)

30(4.5%)

8(12.9%)

33(2.5%)30(2.9%

)3(1.0%)

73(30.0%)

37(28.9%)

36(31.3%)

CD = RCD‡ 608(83.4%)

563(84.4%)

45(72.6%)

1242(93.0%)

967(93.2%)

275(92.6%)

127(52.3%)

69(53.9%)

58(50.4%)

Abbreviations: CD, annual cumulative dose; RCD, annual recommended cumulative dose.‡The annual RCDs according to NICE guidelines were: 2600mg (50mg x 52 weeks) for etanercept; 1120mg (80mg + (40mg x 26 weeks)) for adalimumab and; 270mg (45mg x 6 doses),or 540mg (90mg x 6 doses) if >100Kg, for ustekinumab.p-value* tests for significant differences in the dosing pattern across the three biologic cohorts (combining naïve and non-naïve patients in each biologic cohort).p-value** tests for significant differences in the dosing pattern between naïve and non-naïve patients within each biologic cohort.

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Table 4: Pattern of use of conventional systemic therapies in combination with biologic therapies

Methotrexate

Etanercept(142; 31.0%)

Adalimumab(278; 60.7%)

Ustekinumab(38; 8.3%)

Total(458; 61.2%)

Use of Methotrexate for >120-days 97 (68.3%) 179 (64.4%) 22 (57.9%) 298 (65.1%)

Use of Methotrexate as rescue therapy 27 (19.0%) 66 (23.7%) 6 (15.8%) 99 (21.6%)

Use of Methotrexate as bridging therapy 14 (9.9%) 28 (10.1%) 9 (23.7%) 51 (11.1%)Use of Methotrexate as rescue & bridging therapy

4 (2.8%) 5 (1.8%) 1(2.6%) 10 (2.2%)

CiclosporinEtanercept(73; 33.3%)

Adalimumab(120; 54.8%)

Ustekinumab(26; 11.9%)

Total(219; 29.2%)

Use of Ciclosporin for >120-days 44 (60.3%) 53 (44.2%) 7 (26.9%) 104 (47.5%)

Use of Ciclosporin as rescue therapy 4 (5.5%) 24 (20.0%) 3 (11.5%) 31 (14.2%)

Use of Ciclosporin as bridging therapy 24 (32.9%) 42 (35.0%) 16 (61.5%) 82 (37.4%)Use of Ciclosporin as rescue & bridging therapy

1 (1.4%) 1 (0.8%) 0 (0.0%) 2 (0.9%)

Acitretin

Etanercept(32; 44.4%)

Adalimumab(33; 45.8%)

Ustekinumab(7; 9.7%)

Total(72; 9.6%)

Use of Acitretin for >120-days 20 (62.5%) 17 (51.6%) 4 (57.1%) 41 (56.9%)

Use of Acitretin as rescue therapy 7 (21.9%) 8 (24.2%) 2 (28.6%) 17 (23.6%)

Use of Acitretin as bridging therapy 5 (15.6%) 8 (24.2%) 1 (14.3%) 14 (19.4%)

Fumaric Acid Esters

Etanercept(17; 45.9%)

Adalimumab(17; 45.9%)

Ustekinumab(3; 8.2%)

Total(37; 4.9%)

Use of Fumaric Acid Esters for >120-days 7 (41.2%) 10 (58.8%) 1 (33.3%) 18 (48.7%)

Use of Fumaric Acid Esters as rescue therapy 1 (5.9%) 1 (5.9%) 0 (0.0%) 2 (5.3%)Use of Fumaric Acid Esters as bridging therapy

9 (52.9%) 6 (35.3%) 2 (66.7%) 17 (46.0%)

Hydroxycarbamide

Etanercept(3; 20%)

Adalimumab(9; 60%)

Ustekinumab(3; 20%)

Total(15; 2.0%)

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