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Park, Kim, Yang, Yoon, Kim, Kim, Kim, Oh, Kim, Lee, Choe, Park, and Lee: Comparing Effectiveness Rituximab (MabtheraⓇ) to Other Second-line Biologics for Rheumatoid Arthritis Treatment in Patients Refractory to or Intolerant of First-line Anti-tumor Necrosis Factor Agent: An Observational Study
Original Article

J Rheum Dis 2017;24(4):227-235.

Published online: 31 October 2017

DOI: https://doi.org/10.4078/jrd.2017.24.4.227

Comparing Effectiveness Rituximab (MabtheraⓇ) to Other Second-line Biologics for Rheumatoid Arthritis Treatment in Patients Refractory to or Intolerant of First-line Anti-tumor Necrosis Factor Agent: An Observational Study

Yong-Wook Park1, Ki-Jo Kim2, Hyung-In Yang3, Bo Young Yoon4, Sang Hyon Kim5, Seong-Ho Kim6, Jinseok Kim7, Ji Seon Oh8, Wan-Uk Kim9, Yeon-Ah Lee10, Jung-Yoon Choe11, Min-Chan Park12, Sang-Heon Lee13

1Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Korea

2Division of Rheumatology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea

3Division of Rheumatology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul, Korea

4Department of Rheumatology, Inje University Ilsan Paik Hospital, Goyang, Korea

5Division of Rheumatology, Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea

6Division of Rheumatology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea

7Department of Internal Medicine, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Korea

8Division of Rheumatology, Department of Internal Medicine, National Medical Center, Seoul, Korea

9Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Korea

10Division of Rheumatology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea

11Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea

12Division of Rheumatology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

13Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea

Corresponding to: Sang-Heon Lee, Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea. E-mail: shlee@kuh.ac.kr

Received 12 April 2017       Revised 23 March 2017       Revised 25 May 2017       Accepted 13 June 2017

Copyright © 2017 The Korean College of Rheumatology

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

Failure of first-line anti-tumor necrosis factor (TNF) agents in in rheumatoid arthritis patients leads to decisions among second-line biologic agents. To better inform these decisions, the therapeutic effectiveness of rituximab is compared with other second-line biologic agents in this observational study.

Methods

Between November 2011 and December 2014, study subjects were observed for 12 month periods. Patients with an inadequate response to initial anti-TNF agent received either rituximab or alternative anti-TNF agents (adalimumab/etanercept/infliximab) based on the preference of patients and physicians. The efficacy end point of this study was the change in 28-joint count Disease Activity Score (DAS28) at six and 12 months from baseline. Safety data were also collected.

Results

Ninety patients were enrolled in the study. DAS28 at six months did not change significantly whether the patients were treated with rituximab or alternative anti-TNF agents in intention-to-treat analysis (n=34, −1.63±0.30 vs. n=31, −2.05±0.34) and standard population set analysis (n=31, −1.51±0.29 vs. n=24, −2.21±0.34). Similarly, the change in DAS28 at 12 months did not reach statistical significance (−1.82±0.35 in the rituximab vs. −2.34±0.44 in the alternative anti-TNF agents, p=0.2390). Furthermore, the incidences of adverse events were similar between two groups (23.5% for rituximab group vs. 25.8% for alternative anti-TNF agents group, p=0.7851).

Conclusion

Despite the limitations of our study, switching to rituximab or alternative anti-TNF agents after failure of the initial TNF antagonist showed no significant therapeutic difference in DAS28 reduction.

Keywords: Rheumatoid arthritis, Rituximab, Anti-tumor necrosis factor agent, DAS28 score

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Figure 1.
Study participation diagram. ITT: intention-to-treat, SPS: standard population set.
jrd-24-227f1.tif
Figure 2.
European League Against Rheumatism response after 6 months and 12 months of treatment with rituximab and alternative anti-tumor necrosis factor (TNF) agents.
jrd-24-227f2.tif
Table 1.
Demographic and disease information (intention-to-treat set)
Variable   Rituximab group (n=34) Other anti-TNF agents group (n=31) p-value
Age (yr) Mean±SD   55.62±11.92 52.74±14.36 0.3815§
  Median   60.00 55.00  
  20∼29   0 (0.0) 2 (6.5) 0.2226‡
  30∼39   4 (11.8) 4 (12.9)  
  40∼49   7 (20.6) 7 (22.6)  
  50∼59   6 (17.7) 7 (22.6)  
  60∼69   15 (44.1) 6 (19.4)  
  70∼79   2 (5.9) 5 (16.1)  
Gender Male   9 (26.5) 5 (16.1) 0.3111†
  Female   25 (73.5) 26 (83.9) 　
Smoking status Smoker   5 (14.7) 0 (0.0) 0.1040‡
  Non smoker   26 (76.5) 27 (87.1)  
  UK   3 (8.8) 4 (12.9)  
RF status at baseline Positive   18 (52.9) 19 (61.3) 0.7599‡
  Negative   4 (11.8) 2 (6.5)  
  ND or UK   12 (35.3) 10 (32.3)  
Anti-CCP status at baseline e Positive   15 (44.1) 15 (48.4) 1.0000‡
  Negative   3 (8.8) 2 (6.5)  
  ND or UK   16 (47.1) 14 (45.2)  
Arthroplasty history∗ Hip Yes 3 (8.8) 1 (3.2) 0.1496‡
    No 30 (88.2) 25 (80.7)  
    UK 1 (2.9) 5 (16.1)  
  Knee Yes 1 (2.9) 4 (12.9) 0.3619‡
    No 30 (88.2) 25 (80.7)  
    UK 3 (8.8) 2 (6.5)  
  Elbow Yes 0 (0.0) 2 (6.5) 0.5467‡
    No 30 (88.2) 25 (80.7)  
    UK 4 (11.8) 4 (12.9) 　
  Shoulder Yes 0 (0.0) 0 (0.0) 0.4995‡
    No 30 (88.2) 25 (80.7)  
    UK 4 (11.8) 6 (19.4) 　

Values are presented as number (%). TNF: tumor necrosis factor, SD: standard deviation, RF: rheumatoid factor, CCP: citrullinated protein, ND: not done, UK: unknown.

* The total number of patients is counted by duplication.

† Pearson's chi-square test.

‡ Fisher's exact test.

§ Two sample t-test.

Table 2.
Prescription status at 12 months from second-line biological agents started for each treatment group (intention-to-treat set)
Prescription status Rituximab group (n=34) O Other anti-TNF agents group (n=31) p-value
Initial anti-TNF agents n 34 31  
Adalimumab 17 (50.0) 15 (48.4) 1.0000†
Etanercept 14 (41.2) 13 (41.9)  
Infliximab 3 (8.8) 3 (9.7) 　
Reason for discontinuation of initial anti-TNF agents n 34 31  
No response 9 (26.5) 7 (22.6) 0.8529†
Loss of response 23 (67.7) 21 (67.7)  
Side effects 2 (5.9) 3 (9.7)  
Status of second-line biologics at 6 months n 34 31  
Maintain 31 (91.2) 24 (77.4) 0.0620†
Change 0 (0.0) 5 (16.1)  
Discontinuation 3 (8.8) 2 (6.5)  
Reason for discontinuation of second-line biologics n 3 7  
No response 3 (100.0) 2 (28.6) 0.2083†
Loss of response 0 (0.0) 3 (42.9)  
Side effects 0 (0.0) 2 (28.6)  
Status of second-line biologics at 12 months n∗ 29 21  
Maintain 24 (82.8) 17 (81.0) 0.3389†
Change 4 (13.8) 1 (4.8)  
Discontinuation 1 (3.5) 3 (14.3)  
Reason for discontinuation of second-line biologics n 5 4  
No response 1 (20.0) 1 (25.0) 1.0000†
Loss of response 3 (60.0) 2 (50.0)  
Side effects 1 (20.0) 0 (0.0)  
Other 0 (0.0) 1 (25.0)  

Values are presented as number (%). TNF: tumor necrosis factor.

* In the rituximab and other anti-TNF agents groups, 5 patients who failed to follow up at 12 months are excluded.

† Fisher's exact test.

Table 3.
Change in DAS28 at 6 months comparing to baseline for each treatment group
DAS28 Rituximab Other TNF inhibitors p-value
ITT   n=34 n=31  
Baseline n 34 31  
  Mean±SD 6.35±1.14 5.54±1.14 0.0056∗
  Median 6.35 5.65  
  Min, Max 3.47, 8.35 3.37, 7.95  
6 months n 34 31 　
  Mean±SD 4.46±1.63 3.74±1.40  
  Median 4.13 3.59  
  Min, Max 0.68, 7.54 1.21, 7.17 　
Change n 34 31  
  Mean±SD −1.89±1.73 −1.80±1.53 0.3037†
  LS Mean±SE −1.63±0.30 −2.05±0.34  
  Median −1.91 −1.83  
  Min, Max −6.09, 1.31 −5.09, 1.13  
SPS   n=31 n=24 　
Baseline n 31 24 　
  Mean±SD 6.30±1.18 5.47±1.04 0.0089∗
  Median 6.10 5.49  
  Min, Max 3.47, 8.35 3.37, 7.95  
6 months n 31 24 　
  Mean±SD 4.56±1.51 3.56±1.33  
  Median 4.13 3.37  
　 Min, Max 1.59, 7.54 1.21, 6.98 　
Change n 31 24  
  Mean±SD −1.74±1.59 −1.91±1.53 0.0951†
  LS Mean±SE −1.51±0.29 −2.21±0.34  
  Median −1.86 −1.97  
　 Min, Max −4.76, 1.31 −5.09, 1.13 　

Change is difference between baseline and 6 months. DAS28: disease activity score in 28 joints, TNF: tumor necrosis factor, ITT: intention-to-treat, SPS: standard population set, SD: standard deviation, LS: least squares, SE: standard error.

* Two sample t-test.

† The p-values are based on analysis of covariance models with control for DAS28 and rheumatoid factor of baseline.

Table 4.
Change in DAS28 at 12 months comparing to baseline for each treatment group
  DAS28 Rituximab group (n=24) Other anti-TNF agents group (n=17) p-value
Baseline n 24 17 　
  Mean±SD 6.28±1.27 5.49±0.92 0.0341†
  Median 6.13 5.65  
  Min, Max 3.47, 8.35 3.37, 6.98  
12 months n∗ 22 16 　
  Mean±SD 3.85±1.37 3.10±1.07  
  Median 3.92 3.20  
　 Min, Max 0.01, 6.99 1.21, 5.25  
Change n∗ 22 16  
  Mean±SD −2.30±1.52 −2.29±1.36 0.2390‡
  LS Mean±SE −1.82±0.35 −2.34±0.44  
  Median −2.34 −2.39  
　 Min, Max −5.28, −0.04 −4.70, 0.61 　

Change is difference between baseline and 12 months. DAS2: disease activity score in 28 joints, TNF: tumor necrosis factor, SD: standard deviation, LS: least squares, SE: standard error.

* In the rituximab and other anti-TNF agents groups, 2 patients and 1 patient who have missing data at 12 months are excluded from analysis.

† Two sample t-test.

‡ The p-values are based on analysis of covariance models with control for DAS28 and rheumatoid factor of baseline.

Table 5.
Adverse events on organ systems (intention-to-treat set)
System Organ Class (preferred term) Rituximab group (n=34)
 Other anti-TNF agents group (n=31)
n* (%) Event n* (%) Event
Number of subjects with adverse event (0.7851†) 8 (23.5) 12 8 (25.8) 15
Gastrointestinal disorders 1 (2.9) 1 4 (12.9) 5
Diarrhea 0 (0.0) 0 2 (6.5) 2
Abdominal discomfort 1 (2.9) 1 0 (0.0) 0
Abdominal pain upper 0 (0.0) 0 1 (3.2) 1
Mouth ulceration 0 (0.0) 0 1 (3.2) 1
Nausea 0 (0.0) 0 1 (3.2) 1
Nausea Infections and infestations 0 (0.0)2 (5.9) 0 2 1 (3.2)3 (9.7) 1 4
Upper respiratory tract infection 1 (2.9) 1 1 (3.2) 2
Pneumonia 1 (2.9) 1 0 (0.0) 0
Tuberculosis 0 (0.0) 0 1 (3.2) 1
Urethritis 0 (0.0) 0 1 (3.2) 1
Urethritis Skin and subcutaneous tissue disorders 0 (0.0) 2 (5.9) 0 4 1 (3.2)2 (6.5) 1 2
Erythema 1 (2.9) 1 0 (0.0) 0
Pruritus 1 (2.9) 1 0 (0.0) 0
Rash 0 (0.0) 0 1 (3.2) 1
Skin lesion 1 (2.9) 1 0 (0.0) 0
Skin ulcer 0 (0.0) 0 1 (3.2) 1
Urticaria 1 (2.9) 1 0 (0.0) 0
General disorders and administration site conditions 0 (0.0) 0 2 (6.5) 2
Oedema 0 (0.0) 0 1 (3.2) 1
Pyrexia 0 (0.0) 0 1 (3.2) 1
Respiratory, thoracic and mediastinal disorders 1 (2.9) 1 1 (3.2) 1
Cough 0 (0.0) 0 1 (3.2) 1
Dyspnea 1 (2.9) 1 0 (0.0) 0
Eye disorders 2 (5.9) 2 0 (0.0) 0
Dry eye 1 (2.9) 1 0 (0.0) 0
Iritis 1 (2.9) 1 0 (0.0) 0
Immune system disorders 1 (2.9) 1 0 (0.0) 0
Anaphylactoid reaction 1 (2.9) 1 0 (0.0) 0
Musculoskeletal and connective tissue disorders 0 (0.0) 0 1 (3.2) 1
Back pain 0 (0.0) 0 1 (3.2) 1
Psychiatric disorders 1 (2.9) 1 0 (0.0) 0
Delirium 1 (2.9) 1 0 (0.0) 0
Number of subjects with adverse drug reaction (0.8205†) 4 (11.8) 5 5 (16.1) 7
Skin and subcutaneous tissue disorders 2 (5.9) 3 2 (6.5) 2
Erythema 1 (2.9) 1 0 (0.0) 0
Pruritus 1 (2.9) 1 0 (0.0) 0
Rash 0 (0.0) 0 1 (3.2) 1
Skin ulcer 0 (0.0) 0 1 (3.2) 1
Urticaria 1 (2.9) 1 0 (0.0) 0
Infections and infestations 1 (2.9) 1 2 (6.5) 2
Pneumonia 1 (2.9) 1 0 (0.0) 0
Tuberculosis 0 (0.0) 0 1 (3.2) 1
Tuberculosis Urethritis 0 (0.0)0 (0.0) 0 0 1 (3.2)1 (3.2) 1 1
Gastrointestinal disorders 0 (0.0) 0 2 (6.5) 2
Diarrhea 0 (0.0) 0 1 (3.2) 1
Nausea 0 (0.0) 0 1 (3.2) 1
Immune system disorders 1 (2.9) 1 0 (0.0) 0
Anaphylactoid reaction 1 (2.9) 1 0 (0.0) 0
Respiratory, thoracic and mediastinal disorders 0 (0.0) 0 1 (3.2) 1
Cough 0 (0.0) 0 1 (3.2) 1
Number of subjects with serious adverse reaction (0.8330†) 3 (8.8) 3 0 (0.0) 0
Immune system disorders 1 (2.9) 1 0 (0.0) 0
Anaphylactoid reaction 1 (2.9) 1 0 (0.0) 0
Anaphylactoid reaction Infections and infestations 1 (2.9)1 (2.9) 1 1 0 (0.0) 0 (0.0) 0 0
Pneumonia 1 (2.9) 1 0 (0.0) 0
Respiratory, thoracic and mediastinal disorders 1 (2.9) 1 0 (0.0) 0
Dyspnea 1 (2.9) 1 0 (0.0) 0

Dictionary: MedDRA v17.0. TNF: tumor necrosis factor.

* The total number of patients is counted by duplication.

† The p-values are based on Fisher's exact test.

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