Article Text

Extended report
Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry
1. Henrik Christian Leffers1,2,
2. Mikkel Østergaard1,2,
3. Bente Glintborg3,
4. Niels Steen Krogh4,
5. Heidi Foged5,
6. Ulrik Tarp6,
7. Tove Lorenzen7,
8. Annette Hansen2,8,
9. Michael Sejer Hansen8,
10. Martin Skov Jacobsen9,
11. Lene Dreyer10,
12. Merete Lund Hetland1,2 on behalf of all departments of rheumatology in Denmark
1. 1Department of Rheumatology, Copenhagen University Hospital Glostrup, Glostrup, Denmark
2. 2The Danish Rheumatologic Database (DANBIO), Glostrup, Denmark
3. 3Department of Rheumatology, Holbæk Hospital, Hellerup, Denmark
4. 4Zitelab Aps, Copenhagen, Denmark
5. 5Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark
6. 6Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
7. 7Department of Rheumatology, Vejle Hospital, Vejle, Denmark
8. 8Department of Rheumatology, Copenhagen University Hospital Gentofte, Gentofte, Denmark
9. 9Department of Rheumatology, Randers Hospital, Randers, Denmark
10. 10Department of Rheumatology, Rigshospitalet, Copenhagen, Denmark
1. Correspondence to Henrik Christian Leffers, Department of Rheumatology, Copenhagen University Hospital Glostrup, Nordre Ringvej 57, 2600 Glostrup, Denmark; hsk967{at}alumni.ku.dk

## Abstract

Objectives To describe drug survival, disease activity and clinical response in patients with rheumatoid arthritis (RA) treated with abatacept or tocilizumab in routine care, based on prospectively registered observational data from the nationwide Danish DANBIO registry.

Methods 150 Patients with RA treated with abatacept and 178 treated with tocilizumab were identified. Drug survival was investigated. Response data were available in 104 and 97 patients, respectively. Changes in 28-joint Disease Activity Score (DAS28) based on C-reactive protein (CRP) and European League Against Rheumatism (EULAR) response after 24 and 48 weeks were investigated. No direct comparison of drugs was made.

Results Median (IQR) disease duration was 8.5 (3–14)/9 (3–12) years (abatacept/tocilizumab). 95%/93% of patients had previously received one or more tumour necrosis factor inhibitor (TNFi). After 48 weeks, 54%/64% of patients (abatacept/tocilizumab) maintained treatment. Among patients with available response data, DAS28 was 5.3 (4.7–6.1), 3.4 (2.7–4.9) and 3.3 (2.5–4.3) at baseline, weeks 24 and 48, respectively, in the abatacept group and 5.4 (4.7–6.2), 2.9 (2.3–4.0) and 2.5 (1.9–4.5) in the tocilizumab group. At weeks 24 and 48, the remission rates for abatacept/tocilizumab were 19%/39% and 26%/58%, respectively. EULAR good-or-moderate response rates were 70%/88% and 77%/84%, respectively. The decline in DAS28 variables over time appeared similar between drugs, except for CRP, which seemed to decline more rapidly among tocilizumab-treated patients.

Conclusions In patients with RA (≥90% TNFi failures), a good-or-moderate EULAR response was achieved in ≥70% of patients treated with abatacept or tocilizumab for 24 weeks in routine care. Apparent declines in DAS28 variables over time were similar between drugs, except for the more rapid CRP decline among tocilizumab-treated patients, directly caused by interleukin 6 inhibition.

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## Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, which often causes severe disability and reduced quality of life. During the past decade, the use of tumour necrosis factor inhibitors (TNFi) has improved the treatment of RA significantly, and the high efficacy of TNFi has been demonstrated in several studies.1,,4 However, these drugs have little or no effect in about 30% of treated patients since two-thirds still have moderate or high disease activity after 1 year of treatment.5 Although it has been demonstrated that switching between different TNFi may be beneficial,5 6 treatment alternatives that modify other elements of the inflammatory process seem appealing.

Recently, two biological drugs that are not TNFi have been approved and marketed for the treatment of RA: abatacept and tocilizumab. Abatacept is a fusion protein that binds to B7-molecules (CD80/CD86) on antigen-presenting cells, thereby inhibiting co-stimulation and activation of T cells.7 Tocilizumab is a humanised monoclonal antibody targeted against the interleukin 6 (IL-6) receptor.8

The efficacy and safety of these two drugs in TNFi naïve patients as well as in patients for whom TNFi have failed has been demonstrated in several randomised controlled clinical trials (RCTs),9,,21 but data on their effectiveness in clinical practice are scarce.22 23 Since clinical registries include patients treated in routine care, they provide a valuable supplement to the RCTs, which typically include strictly selected patient groups.

The aim of this study was to describe the drug survival, disease activity, clinical response and predictors thereof in patients with RA treated in routine care with abatacept or tocilizumab, based on prospectively registered observational data from the nationwide Danish DANBIO registry.

## Patients and methods

### Patients

The Danish DANBIO-registry (http://www.danbio-online.dk) is a nationwide registry that was started in 2000 and approved as a clinical quality registry by the Danish National Board of Health in 2006. Registration in DANBIO is mandatory for all Danish departments involved in biological treatment of RA, and DANBIO follows up prospectively >90% of adult patients with RA treated with biological drugs in Denmark.24

The patients included in this study were patients diagnosed with RA according to the American College of Rheumatology (ACR) 1987 criteria,25 who started treatment with abatacept or tocilizumab before 13 April 2010 (abatacept: n=150, tocilizumab: n=178). The patients (n=48) who had been treated with both abatacept and tocilizumab were included in both groups.

### Methods

#### Data collected

From DANBIO, we retrieved the following baseline data: gender, age, disease duration, number and type of previous disease-modifying antirheumatic drugs (DMARDs), number and type of previous biological drugs, Disease Activity Score of 28 joints (DAS28)26 (four variables: swollen joint count (SJC), tender joint count (TJC), C-reactive protein (CRP) (normal level: CRP<10 mg/l according to the detection limit in most centres) and patient global score on a visual analogue scale (VAS)—see DAS28-CRP formula at http://www.das-score.nl, concomitant methotrexate (MTX) and concomitant prednisolone. Furthermore, we retrieved the DAS28, SJC, TJC, CRP, VAS global and Health Assessment Questionnaire (HAQ) score during follow-up at designated time point (described below).

Reasons for drug withdrawal were collected. In an attempt to fill out missing data, we contacted all the rheumatological departments in Denmark asking specifically about patients with missing data. No imputation of missing data was performed.

#### Drug survival

Drug survival was calculated as the number of days individual patients maintained treatment, from start date until date of the first missed dose owing to withdrawal or lack of treatment for ≥3 months. All observations were censored at the last registered visit before 13 April 2010. All patients (150 and 178 for abatacept and tocilizumab, respectively) were included in the survival analysis.

#### Time points

The time points at which patient visits were registered in DANBIO were individual, because of different routines in the clinics. After the baseline visit (0 weeks), the visits were approximated as follows: 6 weeks (range 1–9 weeks), 12 weeks (10–18 weeks), 24 weeks (19–30 weeks), 36 weeks (31–42 weeks) and 48 weeks (43–54 weeks). Consequently, a visit taking place between weeks 10 and 18 was registered as week 12 and so on.6

#### Disease activity and EULAR response

Disease activity was categorised as: DAS28 remission (DAS28<2.6); low disease activity (2.6≤DAS28<3.2), moderate disease activity (3.2≤DAS28≤5.1) and high disease activity (DAS28>5.1).26 Disease activity and European League Against Rheumatism (EULAR) response27 were evaluated at 24 and 48 weeks. Thus, patients who were included in the analysis of disease activity and EULAR response (104 and 97 for abatacept and tocilizumab, respectively) had a measurement of DAS28 at baseline and at least one additional DAS28 measurement within 48 weeks.

#### Statistics

Statistical analyses were carried out using the Predictive Analytics Software program, version 18.0 (SPSS, Chicago, Illinois, USA). For descriptive statistics, medians and IQR are presented. Wilcoxon matched pairs signed rank sum test was used for the comparison of continuous variables.

Kaplan–Meier plots, 95% CI and Cox regression analyses were used for drug survival analysis. Logistic regression analysis with stepwise backward selection was used for the identification of variables at baseline that potentially were associated with (1) low DAS28 at least once within 24 weeks and (2) EULAR good-or-moderate response at least once within 24 weeks. All available baseline variables in DANBIO, including demographics and disease activity parameters, were chosen as explanatory variables. Gender, concomitant MTX use (yes/no) and concomitant prednisolone use (yes/no) were included as categorical variables, whereas age, disease duration, number of previous biological treatments, DAS28 and HAQ score were continuous variables. The same covariates were included in the Cox regression analysis. Owing to the relatively small number of patients in this study, we did not attempt to compare the two drugs statistically. A p value <0.05 was considered statistically significant.

## Results

A total of 150 patients treated with abatacept and 178 patients treated with tocilizumab were included in the study.

The median DAS28 at baseline was 5.3 for abatacept and 5.4 for tocilizumab and the patients had previously received a median of three DMARDs and two biological drugs (table 1). The majority of patients had previously been treated with MTX (abatacept: 95%/tocilizumab: 96%). Nearly all patients had been treated with at least one TNFi (95%/93%). Concomitant MTX at baseline was given to 53% in the abatacept group and 49% in the tocilizumab group, whereas 37% and 31%, respectively, were treated with concomitant prednisolone.

Table 1

Baseline characteristics of patients in the study population*

Median (range) follow-up time was 37 (3–148) weeks and 24 (2–65) weeks for abatacept and tocilizumab, respectively.

### Drug survival

After 24 weeks, 72% (95% CI 65% to 79%) of the 150 patients in the abatacept group and 80% (73% to 87%) of the 178 patients in the tocilizumab group maintained treatment. At 48 weeks, it was 54% (45% to 63%) and 64% (53% to 75%), respectively (figure 1).

Figure 1

Drug survival of abatacept and tocilizumab. The number of patients who withdrew from treatment during follow-up was 67 for abatacept and 41 for tocilizumab. The number of patients still receiving the drug at different time points is shown.

### Disease activity and EULAR response

Of the 150 patients in the abatacept group and 178 patients in the tocilizumab group, 104 and 97 patients, respectively, were eligible for the evaluation of disease activity and EULAR response. The remaining patients either had missing baseline DAS28 registration (n=28/56, abatacept/tocilizumab) or had no follow-up DAS28 registrations mainly owing to short treatment duration (n=18/25, abatacept/tocilizumab). The evaluated patients had the same demographics and disease characteristics as the total number of patients (table 1).

The effects of both drugs on disease activity, DAS28 components, HAQ score and EULAR response are shown in table 2.

Table 2

Disease activity (including DAS28 variables), EULAR response rates and HAQ score at time points (observed data)

#### Abatacept

There was a significant reduction in DAS28 score at all time points (p<0.001) compared with baseline (table 2). The DAS28 was 5.3 (4.7–6.1) median (IQR) at baseline, 3.4 (2.7–4.9) at week 24 and 3.3 (2.5–4.3) at week 48 (table 2 and figure 2A). DAS28 remission rate was 19% at week 24 and 26% at week 48. EULAR good-or-moderate response rates were 70% at week 24 and 77% at week 48.

Figure 2

Measures of disease activity over time. (A) Disease Activity Score in 28 joints (DAS28); (B) swollen joint count; (C) tender joint count; (D) C-reactive protein (CRP); (E) patient visual analogue scale (VAS) global score; (F) Health Assessment Questionnaire (HAQ) score.

#### Tocilizumab

There was a significant reduction in DAS28 score at all time points (p<0.001) compared with baseline (table 2). The DAS28 was 5.4 (4.7–6.2) median (IQR) at baseline, 2.9 (2.3–4.0) at week 24 and 2.5 (1.9–4.5) at week 48 (table 2 and figure 2A). DAS28 remission rate was 39% at week 24 and 58% at week 48. EULAR good-or-moderate response rates were 88% at week 24 and 84% at week 48.

### DAS28 variables and HAQ score

To further explore the patterns of clinical response between the two drugs, we analysed the individual DAS28 variables (SJC, TJC, CRP and patient VAS-global) and HAQ score at each time point for both drugs (table 2 and figure 2A–F). The decline over time in SJCs and TJCs, patients' global scores and HAQ scores was significant at all time points (all p<0.01) and was apparently similar for the two drugs. CRP apparently decreased more rapidly in tocilizumab-treated patients. The reduction in CRP in the abatacept group was only significant after week 24 (p=0.001).

### Prediction of drug survival

To determine predictors of drug survival, we performed a Cox regression analysis (backward stepwise selection) including baseline demographics and disease activity parameters as covariates. We found no statistically significant predictors in the abatacept group (all p>0.05). In the tocilizumab group, higher baseline DAS28 (HR=0.95/DAS28 unit increase (0.91–1.00/DAS28 unit increase), p=0.048) was associated with shorter drug survival.

### Prediction of achievement of low disease activity and EULAR response

#### Abatacept

No statistically significant predictors of low DAS28 were found (all p>0.05), whereas higher age (OR=1.04/year increase (95% CI 1.01 to 1.08/year) p=0.012) was associated with EULAR good-or-moderate response.

#### Tocilizumab

Higher DAS28 at baseline (OR=0.48 (0.32–0.73), p<0.001) was significantly associated with achieving a low DAS28. Lower HAQ score at baseline (OR=2.51 (1.04–6.04), p=0.041) was associated with EULAR good-or-moderate response.

### Discontinuation of treatment

During the follow-up period, 67 (45%) and 39 (22%) patients withdrew from treatment with abatacept and tocilizumab, respectively. A discontinuation summary for both abatacept and tocilizumab is shown in table 3.

Table 3

Discontinuation summary for abatacept and tocilizumab*

#### Abatacept

The number of patients who withdrew from treatment with abatacept owing to adverse events (AEs) was 17, of which four were reported as serious AEs (SAEs).

The SAEs reported for abatacept were: severe acute polyarthritis (n=1); hyperglycaemia and hyponatraemia (n=1); anaphylactic shock (n=1); chest pain and dizziness (n=1).

AEs were raised blood pressure (n=1); raised liver enzymes (n=2); abdominal pain and skin rash (n=1). In nine cases, where AEs were reported as the reason for withdrawal, no further description was given.

#### Tocilizumab

The number of patients who withdrew from treatment with abatacept owing to AEs was 12, of which four were reported as SAEs.

The SAEs reported for tocilizumab were urticaria and chest pain (n=1); skin cancer (n=1); raised liver enzymes and jaundice (n=1); general allergic reaction with palpitations (n=1).

AEs were acute polyarthritis, dizziness and chest pain (n=1); skin rash, raised cholesterol and elevated blood pressure (n=1); sensitivity loss (n=1); worsening of existing infection (n=1).

In four cases, where AEs were reported as the reason for withdrawal, the AE was not described further.

## Discussion

The recent marketing of two new biological drugs, abatacept and tocilizumab, represents interesting new treatment opportunities for patients with RA, who are TNFi resistant. Although RCTs have shown promising efficacy, little is known about the efficacy of the drugs when they are used postmarketing in routine care. This observational study, which was based on data from a nationwide registry, documented the clinical efficacy of abatacept and tocilizumab in patients with RA for whom in >90% TNFi treatment or other biological drugs had previously failed. Abatacept and tocilizumab were found to be good treatment options in such patients. Thus, the disease activity decreased at all time points for both drugs, with remission rates after 24 and 48 weeks of 19% and 26% for abatacept, and 39% and 58% for tocilizumab, respectively. In both treatment groups ≥70% of patients achieved a EULAR good-or-moderate response at 24 weeks of treatment and at 48 weeks it was more than 75%.

Although several RCTs have demonstrated the effect of abatacept, few studies have investigated the efficacy in patients for whom previous TNFi treatment has failed. The Abatacept Trial in Treatment of Anti-TNF inadequate responders (ATTAIN) study from 2005 including only TNFi failures,10 demonstrated a DAS28-ESR (ie, based on the erythrocyte sedimentation rate) remission rate of 10% and a low disease activity rate of 17% after 6 months of treatment. Furthermore, this study demonstrated a significantly improved rate of ACR 20% improvement criteria (ACR20), ACR50 and ACR70 after 6 months of treatment compared with placebo. The Abatacept Researched in RA patients with an Inadequate anti-TNF response to Validate Effectiveness (ARRIVE) study from 2009, also including TNFi failures,20 demonstrated a DAS28-CRP remission rate of 13% and a low disease activity rate of 22% after 6 months of treatment.

Our study showed a slightly higher reduction in DAS28, with a remission rate of 19% and a low disease activity rate of 21% after 24 weeks. In the ATTAIN and ARRIVE studies, however, the mean DAS28 scores at baseline were 6.5 and 6.2, respectively, and 70% and 58% of patients were treated with corticosteroids, which indicates that patients in the RCTs had more severe disease. This apparent difference in baseline characteristics, and the use of intention-to-treat analysis in RCTs compared with our as-observed analysis may, at least in part, account for the different results.

Tocilizumab has also been shown to be effective in several RCTs; however, only one study describes the efficacy in TNFi failures.9 This study demonstrated a DAS28-ESR remission rate of 30% and a low disease activity rate of 21% after 6 months of treatment. Furthermore, EULAR good-or-moderate response rate was 68% after 6 months. This is in accordance with the results from our study where we found a DAS28 remission rate of 39% and a DAS28 low disease activity rate of 16% after 24 weeks of treatment and a EULAR good-or-moderate response rate of 88% at the same time point. We were unable to find any studies of the effect of abatacept among TNFi failures in clinical practice. For tocilizumab we found two studies in which 10% and 78% were TNFi failures, respectively. In the first study 61 participants received tocilizumab as monotherapy. The DAS28-ESR-remission rate was 83.3% after four doses (4 months) and all patients achieved a EULAR good-or-moderate response (100%) at the same time point.22 In a second study the DAS28-ESR-remission rate was 55.2% and the EULAR good-or-moderate response rate was 97% after 24 weeks.23 Why these two clinical studies show such remarkably higher response rates than found in previous RCTs and the rates found in our study is unclear.

When comparing this study with other RCTs and studies in clinical practice, it is important to notice that most of these studies are based on DAS-ESR whereas DAS-CRP was used in our study. It is debated, whether DAS28-CRP yields a lower DAS and a better EULAR response than DAS-ESR.28 29

In previous reports from DANBIO of Danish patients receiving biological treatment, Hjardem et al6 found a EULAR good-or-moderate response rate of 60% after 3 months among patients switching from one TNFi to another. In our study the EULAR good-or-moderate response rates at 12 weeks were 63% and 83% for abatacept and tocilizumab, respectively.

According to this study both drugs seem well tolerated with only a few SAEs. The studies of abatacept and tocilizumab described above, generally report a similar proportion of patients discontinuing owing to SAEs, about 2–3%. As abatacept has been marketed in Denmark since 2007 and tocilizumab since 2009, the follow-up times vary between the two patient groups, and this explains why discontinuations due to SAEs and AEs were reported numerically larger in the abatacept group than in the tocilizumab group. The percentages of patients using concomitant MTX were relatively low (around 50%) in both groups. This is unusual, and one may hypothesise that this may be a result of channelling bias—that is, that the cohorts include many patients with intolerance to several previous biological drugs, and possibly also to MTX.

In Denmark biological treatment is considered in patients with RA for whom DMARDs (mainly MTX) in adequate doses produce an insufficient treatment response, preferably tried in combination with other DMARDs. Usually the first biological treatment is a TNFi, and if the response is insufficient after 3–4 months, the patient is switched to a different biological drug. Treatment with biological drugs can only be prescribed and administered by hospital departments of rheumatology. The expenses are reimbursed by the public health system. In this study, these structural aspects are likely to reduce confounding by indication. Furthermore, data from the DANBIO registry reflect Danish routine practice of biological treatment with a >90% national coverage. This makes DANBIO a suitable tool for assessment of clinical efficacy in real-life settings.

It should be emphasised that it was not possible to directly compare the response rates and drug survivals of abatacept and tocilizumab in this study owing to the non-randomised setting and the relatively small datasets. However, apparent differences in clinical responses and disease activity (as judged by the achievement of EULAR good-or-moderate responses or DAS28 remission) between the two drugs seemed to be caused primarily by a larger decline in CRP in the tocilizumab group. The other DAS28 variables (patient global score, swollen and tender joint counts) and HAQ score seemed similar between the drugs although no direct comparison was made. Since tocilizumab is an IL-6 antagonist, and IL-6 enhances the formation of CRP, our finding raises the question as to whether DAS28 is a valid tool in disease activity assessment of drugs that influence CRP or other variables of the DAS28 directly.

Limitations to this study include missing data arising from varying time points for follow-up visits between hospitals. Furthermore, this study provided no data on the impact on structural damage (ie, radiographic progression). This topic should be investigated in the future.

Based on the findings in this paper, we conclude that patients treated with both abatacept and tocilizumab achieved high response and remission rates and that both drugs represent good therapeutic options in patients with RA refractory to previous TNFi therapy. The response rates were comparable to those found in patients switching to their second TNFi and to the response rates previously demonstrated in RCTs.

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## Footnotes

• Funding HCL received a study grant from the Danish Agency for Science, Technology and innovation, Ministry of Science, Technology and innovation, Denmark (non-commercial).

• Competing interests MLH received consulting fees, speaking fees and/or research grants from Abbott, Centocor, Roche, Schering-Plough, UCB-Nordic and Wyeth (less than US$10 000 each), and on behalf of DANBIO, she has received grants from Abbott, Bristol-Myers Squibb, Roche, Schering-Plough, UCB-Nordic and Wyeth (more than US$10 000 each). MØ received consulting fees, speaking fees and/or research grants from Abbott, Amgen, Bristol-Meyers Squibb, Centocor, Genmab, GlaxoSmithKline, Novo Nordisk, Pfizer, Roche, Schering-Plough, UCB-Nordic and Wyeth (less than US\$10 000 each).

• Provenance and peer review Not commissioned; externally peer reviewed.

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