Original article RHEUMATOLOGY

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1 RHEUMATOLOGY Rheumatology 2015;54: doi: /rheumatology/kev216 Advance Access publication 13 July 2015 CLINICAL SCIENCE Original article Effectiveness and drug adherence of biologic monotherapy in routine care of patients with rheumatoid arthritis: a cohort study of patients registered in the Danish biologics registry Tanja Schjødt Jørgensen 1, *, Lars Erik Kristensen 1,2, *, Robin Christensen 1, Henning Bliddal 1, Tove Lorenzen 3, Michael S. Hansen 4, Mikkel Østergaard 5, Jørgen Jensen 6, Lida Zanjani 5, Toke Laursen 7, Sheraz Butt 8, Mette Y. Dam 9, Hanne M. Lindegaard 10, Jakob Espesen 11, Oliver Hendricks 12, Prabhat Kumar 13, Anita Kincses 14, Line H. Larsen 15, Marlene Andersen 16, Esben K. Næser 3, Dorte V. Jensen 17, Jolanta Grydehøj 18, Barbara Unger 19, Ninna Dufour 20, Vibeke Sørensen 21, Sara Vildhøj 22, Inger Marie Jensen Hansen 23, Johnny Raun 24, Niels Steen Krogh 25 and Merete Lund Hetland 5,26,27 Abstract Objectives. To estimate the prevalence of Danish RA patients currently on biologic monotherapy and compare the effectiveness and drug adherence of biologic therapies applied as monotherapy. Methods. All RA patients registered in the Danish biologics database (DANBIO) as receiving biologic DMARD (bdmard) treatment as monotherapy without concomitant conventional synthetic DMARDs (csdmards) during the study period 1 May, 2011 through 30 April 2013 were eligible for inclusion. All patient files were checked to ensure that they were in accordance with the treatment registration in DANBIO. Descriptive statistics for prevalence, effectiveness and drug adherence of bdmard monotherapy were calculated. Results. Of the 775 patients on bdmard monotherapy, adalimumab (21.3%), etanercept (36.6%) and tocilizumab (15.3%) were the most prevalent biologic agents administered. At the 6-month follow-up, the overall crude clinical disease activity index remission rate in patients still on a biologic drug was 22%, the 28-joint DAS remission rate was 41% and the response rate of those with a 50% improvement in ACR criteria was 28%. At the 6-month follow-up, the drug adherence rates were similar for the different 1 Musculoskeletal Statistics Unit, The Parker Institute, Department of Rheumatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark, 2 Department of Rheumatology, Lund University Hospital, Lund, Sweden, 3 Department of Rheumatology, Diagnostic Centre, Silkeborg Regional Hospital, 4 ReumaKlinik Roskilde, Roskilde, 5 Copenhagen Centre for Arthritis Research, Center for Rheumatology and Spine Diseases, Glostrup Hospital, Glostrup, 6 Department of Rheumatology, Region Hospital Køge, Køge, 7 Department of Rheumatology, Copenhagen University Hospital, Gentofte, 8 Department of Rheumatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, 9 Department of Rheumatology, Aarhus University Hospital, Aarhus, 10 Department of Rheumatology, Odense University Hospital, Odense, 11 Department of Rheumatology, Hospital Lillebælt, Vejle, 12 King Christian 10th Hospital for Rheumatic Diseases, Gråsten, 13 Department of Rheumatology, Sydvestjysk Hospital, Esbjerg, 14 Department of Rheumatology, Copenhagen University Hospital, Rigshospitalet, 15 Department of Rheumatology, Aalborg University Hospital, Aalborg, 16 Department of Rheumatology, Hospital Vendsyssel, Hjørring, 17 Department of Rheumatology, Copenhagen University Hospital, Gentofte, and Bornholms Hospital, Rønne, 18 Department of Rheumatology, Region Hospital Viborg, Viborg, 19 Department of Rheumatology, Region Hospital Horsens, Horsens, 20 Department of Rheumatology, Nordsjællands Hospital, Helsingør, 21 Department of Rheumatology, Region Hospital Randers, Randers, 22 Department of Rheumatology, Region Hospital Holstebro, Holstebro, 23 Department of Rheumatology, Odense University Hospital, Svendborg, 24 Department of Rheumatology, Hospital Lillebælt, Fredericia, 25 ZiteLab ApS, Copenhagen, Denmark, 26 Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen and 27 Danish Rheumatologic Database (DANBIO), Center for Rheumatology and Spine Diseases, Glostrup Hospital, Glostrup, Denmark Submitted 16 October 2014; revised version accepted 30 April 2015 *Tanja S. Jørgensen and Lars E. Kristensen contributed equally to this study. Correspondence to: Henning Bliddal, The Parker Institute, Department of Rheumatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Nordre Fasanvej 57, 2000 Frederiksberg, Denmark. henning.bliddal@regionh.dk! The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Biologic monotherapy in RA bdmards, with the exception of infliximab, which had significantly poorer drug adherence (P < 0.001). The overall drug adherence (except for infliximab) was approximately 70% after 2 years. Conclusion. Nearly one in five (19%) biologic treatments for RA was prescribed in Denmark as monotherapy, of which 70% were on monotherapy from bio-initiation and 30% were on monotherapy after cessation of a concomitant csdmard. Acceptable drug adherence and remission rates were achieved with bdmards. With the exception of infliximab, no statistically significant differences were observed between anti-tnfs and biologics with other modes of action. Key words: rheumatoid arthritis, DMARDs, monotherapy, cohort study, biologics. Rheumatology key messages. Nineteen per cent of biologic treatments for RA were prescribed in Denmark as monotherapy.. In RA patients treated with biologic monotherapy, clinical response and survival on the drug were moderate.. Monotherapy with a biologic DMARD may be an option for treating RA patients not tolerating MTX. Introduction Pharmacological therapy in RA patients includes both conventional (synthetic) DMARDs (csdmards, such as MTX) and biologic DMARDs (bdmards) [1 3]. Both therapies are effective for treating the symptoms and signs of RA and for halting the progression of structural damage [1]. Patients may be treated with bdmards in combination with csdmards or as monotherapy according to guidelines and patient tolerability [1]. Currently nine bdmards are available: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, abatacept, rituximab, tocilizumab and anakinra, with the last four singled out as having modes of action different from the other bdmards [4]. The EULAR recommends the use of a bdmard in patients with poor prognostic features [1]. Except for infliximab and golimumab, which should only be prescribed in combination with MTX or other csdmards, the other bdmards can be given either as monotherapy or in combination with MTX [2]. Previous studies have demonstrated that between 10% and 30% of RA patients are MTX intolerant; discontinuation of MTX is common in clinical practice [5]. For patients who are intolerant to MTX, bdmard monotherapy may be appropriate. Our objective was to use data from the nationwide Danish biologics (DANBIO) database to estimate the prevalence of bdmard monotherapy in Danish RA patients, comparing the different bdmards given as monotherapy for effectiveness and drug adherence and identifying predictors of remission. Results based on DANBIO data, which cover >90% of rheumatology patients treated with bdmards [6], can be considered representative of patients with RA who are treated in routine care. Methods Eligibility criteria, data summaries and statistical analyses were performed based on a predefined protocol. The primary outcomes were Clinical Disease Activity Index (CDAI) remission after 6 months of follow-up. Secondary outcomes included 28-joint DAS (DAS28) remission; 20%, 50% and 70% ACR response criteria (ACR20, ACR50, ACR70) and drug adherence rates after 6 months. The manuscript was prepared according to the recommendations from the Enhancing the Quality and Transparency of Health Research network [7], with a focus on reporting a cohort study [8, 9]. According to Danish law, informed consent and ethics approval were not required for the present study. Study design, setting and participants RA patients who were registered in DANBIO [10] as receiving treatment with any bdmard without concomitant csdmard therapy (i.e. monotherapy) in the period from 1 May 2011 to 30 April 2013 were included in the present study. The patients were continuously enrolled and were monitored in DANBIO at baseline and during treatment. The patients were seen in the clinics at individual time points. After the baseline visit (0 months), the visits were approximated as follows: 0.5 month (range 1 4 weeks), 1.5 months (range 5 9 weeks), 3 months (range weeks) and 6 months (range weeks). If more than one visit had occurred during the period, the visit closest to the approximated month was selected [11]. Patients were followed for 6 months (range 5 10 months) after initiation of the first dose of biologic monotherapy treatment. Withdrawals from treatment were routinely recorded by the treating physicians and classified as being due to adverse events, lack of response/inefficacy or miscellaneous reasons such as pregnancy, patient decision, poor compliance and other unspecified causes. No formal criteria were required to terminate treatment, and the decision was based on the judgement of the treating physician. All departments of rheumatology were invited to participate and validate data by nominating a responsible local physician [12]. Participating departments audited patient files for correctness of data entry. DANBIO data were validated with respect to monotherapy timelines for date of onset (first dose bdmard administered), dosage for the bdmard monotherapy and, in cases of withdrawal, the date of the first missing dose

3 Tanja Schjødt Jørgensen et al. The study population included patients who initiated bdmard therapy during the study period (incident monotherapy) and patients who had initiated bdmard therapy prior to the study period (prevalent monotherapy). Variables At the time of inclusion into DANBIO, the following core data were recorded: diagnosis, year of disease onset, previous and concomitant csdmard treatment and systemic prednisolone dosage. At treatment start (baseline) and at each follow-up visit, the CDAI was calculated [13]. In addition, the following clinical data were registered: HAQ, patient-scored visual analogue scale for pain (VASpain), patient-scored VAS for general health (VASglobal), physician s global assessment of disease activity scored on a VAS, 28 tender and swollen joint counts, and CRP. CDAI, DAS28, ACR20, ACR50 and ACR70 were calculated at 6 months of follow-up. Remission was assessed in two ways: patients with a CDAI score of <2.8 [13] or a DAS28 score of <2.6 [14] at follow-up were considered to be in remission. Statistical analyses Data were analysed by Kruskal Wallis test for betweengroup comparisons regarding continuous variables, and a chi-squared test was used for categorical variables. For the discrete treatment outcomes, both per-protocol and intent-to-treat (ITT)-corrected data [using the LUNDEX (an index of the proportion of patients who not only remain on a particular therapeutic regimen but also fulfil certain response criteria) [15] are given. The LUNDEX adjustment is an ITT method developed for the observational setting to account for both withdrawals from therapy and missing response recordings at certain points of follow-up [15]. Drug adherence data were estimated by Kaplan Meier plots and further analysed with log-rank statistics for comparing different treatments. Simple and multivariable Cox proportional hazard models were used to investigate the effect of possible risk factors for treatment termination. Post hoc analysis stratified for prevalent and incident monotherapy was performed. The multivariable Cox proportional model was designed using stepwise backward deletion of covariates (Table 1) with P > 0.1. The following significant variables were then entered into the Cox regression analyses: sex, prednisolone usage (yes/no) and type of bdmard. Independent predictors of clinical response at 6 months were identified using a multivariable, binary, logistic regression model based on a priori assumptions of significant predictors: age, sex, type of bdmard, number of previous bdmard courses, prednisolone usage (yes/no) and MTX usage prior to monotherapy. The level of significance was chosen to be P < Results Patients and prevalence of biologic monotherapy Twenty-one (84 %) of the 25 Danish rheumatology departments participated in the study. During the study period, a total of 4744 RA patients were registered in DANBIO as being on bdmard treatment, of which 4151 (87.5%) were treated in the participating departments. Of these, 1000 (24.1%) were registered in DANBIO as receiving bdmard monotherapy and thus were eligible for inclusion. We excluded 225 (22.5%) patients after file review due to use of concomitant csdmards not registered in DANBIO, leaving 775 (18.7%) in verified bdmard monotherapy. A total of 545 (70%) of the 775 participants were on monotherapy from biologic therapy initiation and 230 (30%) were on monotherapy after cessation of concomitant csdmard. A total of 248 patients were incident and 485 were prevalent on bdmard monotherapy. The number of patients on bdmard monotherapy varied across the efficacy and drug adherence measures, as 42 patients lacked one or more variables at follow-up. The study population was representative of a typical RA population (Table 1). Most of the patients were women, with a mean age of 56 years. More than 70% were RF positive and the average disease duration was >12 years. On average the patients had previously been treated with four different DMARDs almost 90% with MTX in doses of mg/week. Approximately half of the patients were initiating their first biologic agent, 22% their second and 25% their third. A total of 22% received prednisolone. At the time of inclusion, their disease activity was moderate, with a CDAI of 21.1, Simple Disease Activity Index of 23.3 and DAS28 of 4.4. The patients were moderately disabled, with an average HAQ score of 1.3 (Table 1). Of the 775 patients on monotherapy, adalimumab (21.3%), etanercept (36.6%) and tocilizumab (15.3%) were the most prevalent (Fig. 1) biologic agents administered. The number of patients treated with each biologic agent is shown in Fig. 1. Treatment responses at 6 months At the 6-month follow-up, the crude CDAI remission rate in patients still on the biologic drug ranged from 0% (abatacept) to 28% (adalimumab), the DAS28 remission rate ranged from 17% (abatacept) to 56% (golimumab), the ACR50 response rate ranged from 14% (infliximab) to 38% (abatacept) and the ACR70 response rate ranged from 0% (abatacept) to 19% (adalimumab) (Table 2). Although the rates were numerically different, the results did not attain statistical significance. Overall, the crude CDAI remission rate after 6 months was 22%, declining to 19% when corrected for LUNDEX (Table 2). The average CDAI change was 11. For DAS28 remission, the crude and LUNDEX corrected rates were 41% and 35%, respectively. The crude response rates for ACR20, ACR50 and ACR70 were 40%, 28% and 11%, respectively (Table 2). The stratified post hoc analysis showed that neither incident nor prevalent monotherapy status at commencement of the study was associated with CDAI remission rates. Drug adherence A total of 175 patients withdrew from treatment during the 6 months of follow-up (Fig. 1). At the 6-months follow-up,

4 Biologic monotherapy in RA TABLE 1 Baseline characteristics and disease activity of patients in the study population according to treatment Abatacept (N = 17) Adalimumab (N = 165) Certolizumab (N =26) Etanercept (N = 284) Golimumab (N = 21) Infliximab (N = 48) Rituximab (N =92) Tocilizumab (N = 119) Total (N = 772) Characteristic n n n n n n n n n Female sex, n (%) 14 (82) (75) (88) (76) (62) (83) (82) (76) (77) 772 Age, years 54.0 (11.9) (13.2) (12.8) (12.7) (14.8) (14.2) (10.8) (13.4) (12.9) 740 IgM RF positive, n (%) 14 (82) (62) (54) (71) (67) (65) (80) (81) (71) 772 Disease duration, years 16.3 (9.5) (11.2) (12.5) (10.6) (8.4) (10.6) (11.9) (9.3) (10.8)** 686 No. of previous DMARDs 4.6 (2.7) (2.1) (2.4) (2.2) (2.4) (2.2) (2.6) (2.3) (2.3)** 740 Previous use of MTX, n (%) 15 (88) (85) (81) (89) (90) (85) (92) (87) (88) 772 MTX maximum dosage, mg 13.5 (7.2) (16.9) (6.9) (6.2) (7.6) (6.5) (6.9) (11.4) (10.1) 740 Concomitant prednisolone, n (%) 6 (35) (21) (23) (20) (14) 21 6 (13) (29) (24) (22) 772 No. of previous biologics 3.7 (1.8) (0.7) (1.0) (0.8) (1.4) (0.6) (1.7) (1.5) (1.3) 740 Biologic treatment, series, n (%) First series 1 (6) 106 (64) 19 (73) 151 (53) 9 (43) 39 (81) 17 (19) 31 (26) 373 (48)** Second series 3 (18) 40 (24) 3 (12) 79 (28) 3 (14) 3 (6) 20 (22) 21 (18) 172 (22) Third series 13 (77) 10 (6) 3 (12) 35 (12) 9 (43) 4 (8) 52 (57) 65 (55) 191 (25) Missing 0 (0) 17 9 (6) (4) (7) (0) 21 2 (4) 46 3 (3) 89 2 (2) (5) 736 Swollen joint count (0 28) 4.3 (4.1) (4.6) (2.5) (5.4) (4.1) (4.3) (5.1) (4.5) (4.9) 625 Tender joint count: (6.1) (6.4) (7.7) (7.6) (6.7) (8.5) (7.3) (7.5) (7.4) 627 CRP, mg/l 15.9 (15.2) (38.2) (8.4) (26.5) (41.4) (11.6) (35.4) (29.7) (30.3) 628 Patient global assessment 49.5 (31.1) (29.3) (25.2) (28.1) (29.8) (29.1) (27.9) (28.8) (28.6)** 618 (0 100 mm VAS) HAQ score 1.3 (0.5) (1.0) (0.6) (0.8) (0.8) (0.9) (0.8) (0.8) (0.8)** 605 CDAI 18.0 (13.3) (13.7) (11.3) (15.3) (14.0) (15.6) (14.8) (14.3) (14.5) 565 SDAI 19.5 (14.5) (15.4) (11.6) (16.5) (16.8) (15.9) (17.1) (15.9) (15.9) 556 DAS (1.8) (1.6) (1.4) (1.6) (1.7) (1.6) (1.5) (1.7) (1.6) 598 Data are given as mean (S.D.) unless otherwise indicated. **Statistically significant difference between the different biologic agents (P < 0.05). CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index; VAS: visual analogue scale

5 Tanja Schjødt Jørgensen et al. FIG. 1Study population (flow diagram) TABLE 2 Effectiveness of different biologics at the 6-month follow-up Characteristic Abatacept (n = 12) Adalimumab (n = 132) Certolizumab (n = 13) Etanercept (n = 229) Golimumab (n = 20) Infliximab (n = 33) Rituximab (n = 72) Tocilizumab (n = 89) Total (n = 600) CDAI remission n Remission, n (%) 0 (0) 35 (28) 1 (10) 46 (21) 4 (25) 2 (6) 10 (15) 23 (27) 121 (22) b LUNDEX corrected, % CDAI, mean (S.D.) 10.2 (12.5) 13.4 (13.6) 5.1 (7.7) 11.9 (14.9) 13.4 (15.4) 8.4 (12.5) 7.3 (16.4) 9.8 (13.7) 11.1 (14.4) b DAS28 remission n Remission, n (%) 2 (17) 65 (50) 3 (27) 99 (44) 9 (56) 8 (24) 14 (19) 42 (47) 242 (41) b LUNDEX corrected, % ACR response n ACR20, n (%) 3 (38) 44 (48) 2 (33) 66 (42) 5 (46) 4 (18) 14 (32) 25 (39) 163 (40) b LUNDEX corrected, % ACR50, n (%) 3 (38) 31 (34) 2 (33) 48 (31) 4 (36) 3 (14) 7 (16) 17 (27) 115 (28) b LUNDEX corrected, % a ACR70, n (%) 0 (0) 17 (19) 0 (0) 28 (18) 0 (0) 1 (5) 2 (5) 10 (16) 58 (14) b LUNDEX corrected, % a CDAI remission, DAS28 and ACR responses are given as n (%). b Non-significant. CDAI: Clinical Disease Activity Index; DAS28: 28-joint DAS; ACR20/50/70: 20%, 50% and 70% ACR criteria response, respectively; LUNDEX: an index of the proportion of patients who not only remain on a particular therapeutic regimen but also fulfil certain response criteria. drug adherence rates were similar for the various bdmards with the exception of infliximab, which had significantly poorer drug adherence (P < 0.001) (Fig. 2A). The overall drug adherence (except for infliximab) was 80% after 6 months, declining to 70% after 2 years (Fig. 2A). For some of the drugs (abatacept, certolizumab and golimumab), the number of patients was low and follow-up time was short (Fig. 2A). Post hoc analysis of drug adherence rates was stratified for prevalent (data not shown) and incident (Fig. 2B)

6 Biologic monotherapy in RA FIG. 2Drug adherence, stratified by drug (A) All cases (both incident and prevalent cases) and (B) only the incident cases (patients who initiated bdmard during the study period). The graph for the Kaplan Meier estimated survival in (A) has been censored when n < 10. The number of patients on a drug at different time points is listed below the figure

7 Tanja Schjødt Jørgensen et al. FIG. 3Drug adherence, stratified by first-, second- and third-line biologic monotherapy The graph for the Kaplan Meier estimated survival has been censored when n < 10. The number of patients on a drug at different time points is listed below the figure. monotherapy and showed similar results with no statistically significant differences between drugs. Drug adherence rates were independent of the number of biologic treatments the patients had received previously (Fig. 3). Predictors of treatment response and drug adherence Logistic regression analysis showed that concomitant prednisolone treatment (yes/no) [odds ratio (OR) 0.56 (95% CI 0.32, 0.98), P = 0.04] and higher age (per year) [OR 0.98 (95% CI 0.96, 0.99), P = 0.01] were negative predictors of CDAI remission, whereas male sex [OR 1.31 (95% CI 0.82, 2.09), P = 0.26], previous use of MTX (yes/no) [OR 1.15 (95% CI 0.54, 2.46), P = 0.72], number of previous bdmards [OR 0.95 (95% CI 0.77, 1.18), P = 0.64] and bdmards (P = 0.18) were not. In addition, the Cox proportional hazards model showed that male sex [hazard ratio (HR) 0.73 (95% CI 0.54, 0.99), P = 0.045] and concomitant use of prednisolone [HR 1.41 (95% CI 1.07, 1.86), P = 0.015] were statistically significant predictors for drug withdrawal. Furthermore, the risk of withdrawal was increased for infliximab compared with the different bdmards [HR 2.53 (95% CI 1.70, 3.77), P < 0.001]. Discussion In the present study, which was based on data from the nationwide DANBIO registry, we found that approximately one in five biologic treatments for RA was prescribed as monotherapy (i.e. without concomitant csdmards). Monotherapy was most prevalent for patients treated with adalimumab, etanercept and tocilizumab. Our main finding was that in RA patients receiving biologic monotherapy, there was no significant difference between the various bdmards regarding remission and drug retention rates. CDAI remission rates tended to be highest for adalimumab, etanercept, golimumab and tocilizumab, and lowest for abatacept, certolizumab and infliximab, with rituximab in between. Overall, the remission and response rates in the present study were similar in the stratified sensitivity analysis, although somewhat lower than in previously published studies in bdmard combination therapy with MTX [12, 16 22]. Three of the four bdmards labelled for monotherapy (adalimumab, etanercept and tocilizumab) achieved the highest CDAI remission rates, whereas abatacept, certolizumab and infliximab achieved the lowest remission rates, although not statistically significant. These observations are in agreement with results from previous observational studies of bdmard combination therapy with MTX, where adalimumab, etanercept and tocilizumab had higher remission rates than abatacept and infliximab [12, 16, 22]. Drug adherence is regarded as a measure of treatment effectiveness [23, 24]. The overall retention rate after 2 years was 70%, which is generally lower than previously

8 Biologic monotherapy in RA published in studies of combination therapy [16, 18 21, 25]. The poor performance of infliximab was expected, since it is not recommended for monotherapy [2]. Thus the patients who received infliximab as monotherapy were likely to be a highly selected subgroup. Surprisingly, we found that retention rates were independent of treatment series. Patients who were in their second or third line of bdmard as monotherapy adhered to the treatment as long as those who were on their first biologic agent on monotherapy. This finding contrasted with data from the Spanish BIOBADASER registry on patients in combination therapy, which showed that drug survival in switchers was lower than in anti-tnf-naive patients [26]. Furthermore, a large observational study on drug survival demonstrated an increased risk of withdrawal from the second treatment for the same reason as the first, regardless of whether it was due to inefficacy or adverse events [27]. The pooling of anti-tnf bdmards and bdmards with other modes of action in the present analysis may have influenced drug survival in either direction for switchers. Another possibility might be that adherence to monotherapy depends more on other factors (e.g. patient age and co-morbidities). We found that concomitant prednisolone treatment and higher age were negative predictors for achieving CDAI remission. Prednisolone is often considered a surrogate marker for disease severity. Limitations and strengths The non-randomized observational design of this study has limitations such as possible bias regarding patient selection and assignment of treatment. As demonstrated in the Swedish registry [28], patients with many comorbidities could have been channelled to non-tnf biologics, hampering the effectiveness of these drugs. Moreover, anti-tnf has previously been a first-line treatment in RA, wherefore non-tnfs have been used more as second- or third-line treatment, potentially deflating the response and adherence to these biologics. In addition, decisions to start or stop bdmards as well as concomitant csdmards were based solely on clinical practice, experience and the judgement of treating physicians, with national guidelines as a support. The overall drug adherence analysis comprised both incident and prevalent monotherapy courses, therefore subgroup analyses were performed with stratification for both of these two monotherapy courses. For external comparison of drug adherence rates from this study, the incident monotherapy rates should be used. Although these methodological limitations should be taken into account when interpreting the results, observational studies remain important contributors of information from daily clinical practice. The relatively small numbers of patients treated with each biologic involve the risk of type 2 error. On the other hand, the nationwide prospective collection of uniform and standardized data is a strength that makes generalizability of the results reasonable. DANBIO depends on voluntary reporting from clinicians. The data in our study were generally in agreement with the patient files. It was beyond the scope of this study to fully validate all entries in DANBIO, and therefore the true prevalence of monotherapy is likely to be higher than 19%. However, we have no reason to believe that the cases included were systematically different from the rest. Conclusion In conclusion, this observational study showed that close to one in five biologic treatments for RA in Denmark was prescribed as monotherapy. Of these, 70% were on monotherapy from biologic therapy initiation and 30% were on monotherapy after cessation of concomitant csdmard. With the exception of infliximab, there was no significant difference between the various bdmards concerning remission rates and drug adherence in patients treated with biologic monotherapy. Remission rates and drug adherence were acceptable, with an overall CDAI remission rate of 22%, a DAS28 remission rate of 41%, an ACR50 response rate of 28% and a 70% retention rate after 2 years. We also found that drug adherence rates were independent of the previous number of biologic treatments. Thus monotherapy with a bdmard may be an option for treating RA patients not tolerating MTX or other csdmards. Acknowledgements The authors as listed on the title page of the manuscript have all made substantial contributions that qualify them as authors. R.C., H.B., T.L., M.S.H. and M.Ø. contributed to the conception and design, interpretation of data, drafting the article and revising it critically for important intellectual content. T.S.J., L.E.K. and M.L.H. contributed to the collection of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content. J.J., L.A.Z., T.L., S.B., M.Y.D., H.M.L., J.E., O.H., P.K., A.K., L.H.L., M.A., E.K.N., D.V.J., J.G., B.U., N.D., V.S., S.V., I.M.J.H., J.R. and N.S.K. contributed to the collection of data, drafting the article and revising it critically for important intellectual content. All authors have read and approved the final version. Funding: This study was supported by unrestricted grants from Roche, The Oak Foundation and the University of Lund (Sweden). The sponsors had no role in the design, collection, analysis or interpretation of data; in drafting of the manuscript or in the decision to submit the manuscript for publication. Disclosure statement: M.L.H. has received consulting fees from Pfizer, Roche and MSD. M.Ø. has received consulting fees and/or honoraria and/or research support from Abbott/AbbVie, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Janssen, Merck, Mundipharma, Novo Nordisk, Pfizer, Schering-Plough, Roche UCB and Wyeth. L.E.K. has received consultancy fees and fees for speaking from AbbVie, Bristol-Myers Squibb, MSD and Pfizer. R.C. has received consulting fees and/or honoraria and/or research support paid to his institution from

9 Tanja Schjødt Jørgensen et al. Abbott/AbbVie, Bristol-Myers Squibb, Janssen, MSD, Mundipharma, Novartis, Pfizer and Roche. T.L. has received consultancy fees from Roche and Pfizer. M.S.H. has received consultancy fees from AbbVie and Roche. H.B. has received consulting fees and/or grants from AbbVie, Roche, Pfizer, Novo Nordisk and BMS. All other authors have declared no conflicts of interest. References 1 Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73: Singh JA, Furst DE, Bharat A et al update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012;64: Nam JL, Ramiro S, Gaujoux-Viala C et al. 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