Abstract
Objectives. We examined whether the addition of another conventional disease-modifying anti-rheumatic drugs (DMARDs) to methotrexate (MTX) upon infliximab (IFX) discontinuation in well-controlled rheumatoid arthritis (RA) patients could suppress subsequent disease flare.
Methods. RA patients maintaining DAS28-CRP (Disease Activity Score of 28 joints with C-reactive protein) scores < 2.6 for ≥ 6 months with IFX were randomized either to receive addition of bucillamine (BUC) to MTX (BUC + MTX group; n = 24) or not (MTX group; n = 31) upon discontinuing IFX. The primary endpoint was the flare rate within 2 years of IFX discontinuation.
Results. Six patients discontinuing MTX during the study were excluded from analyses. Seventeen patients (63.0%) experienced flares in the MTX group, which was significantly reduced in the BUC + MTX group (31.8%; p = 0.045). Further, the flare rates differed significantly between remission and non-remission by a Boolean definition upon IFX discontinuation in the MTX group (40.0% vs. 91.7%, respectively; p = 0.014), but they were comparable in the BUC + MTX group. BUC treatment was interrupted in seven patients due to rash, proteinuria and incompliance.
Conclusions. DMARDs combination therapy may be a better treatment strategy than MTX monotherapy for maintaining RA control after successful discontinuation of biological agents.
Introduction
Rheumatoid arthritis (RA) is characterized by persistent polyarthritis and presence of autoantibodies to post-translationally modified self-antigens, such as citrullinated proteins [Citation1]. Early and aggressive treatment strategies targeted at achieving clinical remission or at least low disease activity as well as the introduction of biological agents in RA therapy have successfully led to achievement of radiographic and functional remission in a significant portion of RA patients [Citation2]. However, the staggering expense of biological agents often limits their use to severe and refractory patients [Citation3].
From a socio-economical point of view, the limited utility of biological agents for a specific period of the clinical course gives legitimate reason to seek improved cost-effectiveness. Although anti-tumor necrosis factor (anti-TNF) biological agents such as infliximab (IFX) have been successfully withdrawn in early RA patients [Citation4,Citation5], rarely can they be discontinued without subsequent disease flare in RA patients who have shown an inadequate response to MTX [Citation6,Citation7]. One exception comes from the RRR (remission induction by Remicade in RA) study, which demonstrated the potential for maintenance of disease control after discontinuation of IFX therapy in RA patients who had a mean disease duration of 7.7 years [Citation8]. However, even in that study, flare developed in 45% of RA patients within the relatively short follow-up period of 1 year after discontinuation of IFX.
We have therefore conceived a clinical trial to determine whether or not the addition of another non-biological disease-modifying anti-rheumatic drug (DMARD) is useful in the maintenance of RA remission or low disease activity and in the suppression of disease flare after discontinuation of IFX. Bucillamine (BUC) was chosen because previous studies have suggested its usefulness in combination with MTX [Citation9,Citation10]. BUC is a d-penicillamine derivative agent (2-mercapto-2-methylpropanoyl-L-cystein) which contains two thiol residues. The mode of action of BUC has been reported to regulate T-cell [Citation11,Citation12] and B-cell function [Citation13], suppress interleukin (IL)-6, IL-8 and IL-1β formation [Citation14,Citation15], and suppress vascular endothelial growth factor formation [Citation16].
Here we report the first results from the BUC Study of Holding remission after IFX Dose-Off (BuSHIDO) trial, evaluating the treatment strategy of DMARD combination therapy after successfully achieving disease control using biological agents (ClinicalTrials.gov Identifier NCT00716248).
Patients and methods
Patients
RA patients (aged ≥ 20 years) in whom at least six doses of IFX had resulted in satisfactory control of disease activity were eligible to participate in this study. “Satisfactory control of disease activity” was defined as Disease Activity Scores of 28 joints using a C-reactive protein score (DAS28-CRP) < 2.6 or, when CRP values were not available, a DAS28-erythrocyte sedimentation rate (ESR) < 3.2, because of the reported correspondence of DAS28-CRP value of 2.7 to DAS28-ESR value of 3.2 [Citation17]. Maintenance of these values on each infusion visit for ≥ 6 months was required for inclusion in the study. All patients satisfied the 1987 American College of Rheumatology (ACR) revised criteria for the classification of RA [Citation18]. Exclusion criteria were contraindications to BUC, including hematological and renal disorders, and a history of adverse events with BUC.
Study design
This open, randomized, controlled, single center study was performed in compliance with the Helsinki Declaration, with the approval of the Ethics Committee of Saitama Medical Center, Saitama Medical University. Registration of patients in this study commenced in January 2007 and was completed on December 31, 2009. Patients who provided written informed consent for participation in the study were randomly allocated to the BUC + MTX group (addition of BUC upon IFX discontinuation) or MTX group (no BUC) (). BUC was administered at 100 mg twice a day. The dosing method and dosage of other drugs including MTX were unchanged throughout the study period.
Figure 1. Disposition of randomized patients through the 2 years. Patients who discontinued MTX were excluded from further analyses.
The following parameters were analyzed every 3 months: swollen joint count (SJC), tender joint count (TJC), patient global assessment of disease activity (PGA), physician global assessment of disease activity (PhGA), Health Assessment Questionnaire-disability index (HAQ-DI) score, and serum levels of CRP and matrix metalloproteinase-3 (MMP-3) as well as ESR. In addition, a modified total Sharp score (mTSS) was examined for baseline radiographic damage by two experienced evaluators [Citation19], and the average of their ratings was taken.
Primary endpoint
The primary endpoint of the study was the disease flare rate within the 2-year follow-up period. Disease flare was defined by meeting both DAS28-CRP ≥ 2.6 and DAS28-ESR ≥ 3.2.
Statistical analyses
A sample size of 25 patients per treatment group was first calculated to provide 80% power (α = 0.05, β = 0.2) with a 10% non-completion rate for the 2 years of IFX discontinuation. This calculation assumed that the flare rate would be 20% in the BUC + MTX group and 65% in the MTX group. The proportions of participants who met the given criteria were compared with Fisher's exact test or χ2 test, while Wilcoxon's rank sum test was used to compare continuous data. The Kaplan–Meier analysis and log-rank test were used for the comparison of survival curves between groups. All statistical analyses were performed using SAS software version 9.2 (SAS Institute Inc., Cary, NC, USA).
Results
Patient disposition and overall safety
Of the 55 patients enrolled in the present study (MTX group, n = 31; BUC + MTX group, n = 24; ), six who discontinued MTX before the primary endpoint were excluded from the following analyses, comprising four and two patients in the MTX and BUC + MTX groups, respectively, due to the risk of teratogenicity in childbirth (n = 3), MTX-associated lymphoproliferative disease (MTX-LPD) at 12 months (n = 1) and noncompliance (n = 2). BUC was interrupted in another seven patients because of rash (n = 5), reversible proteinuria (n = 1) and noncompliance (n = 1). Those seven patients were followed-up for disease flare during the study period. No other clinically relevant adverse events were reported.
Baseline demographic and clinical features
Baseline (0 months at the time of IFX discontinuation unless otherwise stated) demographic and clinical features of the 55 patients were analyzed and compared between treatment groups (). All demographic and clinical features were similar between groups, including gender ratios, age, disease duration, serological state, disease activity, physical disability, joint damage, and the dose of concomitant MTX and prednisolone. The one exception was the baseline DAS28-CRP value, which was lower in the BUC + MTX group (1.3 ± 0.3) than in the MTX group (1.6 ± 0.5; p = 0.011), which had considerably improved from that at start of IFX in the both groups ().
Table 1. Baseline characteristics of randomized patients.
Primary endpoint
The flare rate after IFX discontinuation for 2 years was compared between the two treatment groups for primary endpoint analysis. The flare rate was 63.0% in the MTX group, which was significantly greater than the rate of 31.8% in the BUC + MTX group (p = 0.045 by Fisher's exact test; ), indicating that the primary endpoint was met. In addition, the flare rate within 2 years was 26.7% in patients continuing BUC but 42.9% in those who had BUC treatment interrupted due to adverse events, suggesting the potential importance of BUC continuation in maintaining disease control.
Figure 2. Effects of BUC on the flare rate after IFX discontinuation. *P = 0.045 versus MTX group by Fisher's exact test.
Cumulative disease flare and adverse events during the 2 years
Using Kaplan–Meier survival curve analyses, we investigated and compared the time points of disease flare and adverse events, both of which are used to evaluate usefulness of ongoing treatments. Continuation of allocated treatment was not significantly different between treatment regimens (p = 0.427 by Log-rank test; ). However, comparisons of time-dependent disease flare between groups confirmed significantly less disease flare in the BUC + MTX group than in the MTX group (p = 0.017, Log-rank test; ). Of note, all six instances of discontinuing BUC due to adverse events occurred within the first 6 months.
Figure 3. Comparison of treatment survival by Kaplan–Meier analysis. (A) Overall treatment survival was compared between BUC + MTX (circles connected by solid lines) and MTX groups (squares connected by dashed lines). P = 0.427 by Log-rank test. (B) Treatment survival focused on flare favored the BUC + MTX group (circles connected by solid lines) over the MTX group (squares connected by dashed lines). *P = 0.017 by Log-rank test.
Factors associated with disease flare
In the analysis of differences in background variables with respect to the presence or absence of flare among the entire population for efficacy analysis (n = 49), TJC, SJC, PGA and DAS28-CRP upon IFX discontinuation differed significantly between the flare-positive and flare-free groups (). Regarding the MTX group, TJC, PGA, PhGA and DAS28-CRP at IFX discontinuation were significantly greater in the flare-positive group than in the flare-free group. In contrast, no significant differences in background variables were demonstrated between flare-positive and flare-negative patients in the BUC + MTX group.
Table 2. Comparisons between patients with and without flares.
Flare rate stratified by remission status
Because some patients had minimal disease activity, namely not in remission, upon IFX discontinuation and the baseline DAS28-CRP value was slightly higher in the MTX group compared with the BUC + MTX group (), we compared flare rates stratified by remission status according to ACR/EULAR (European League Against Rheumatism) Boolean criteria for RA remission, which are regarded as stringent remission criteria [Citation20]. The frequency of remission at IFX discontinuation was not significantly different between treatment groups. Interestingly, 11 of 12 (91.7%) patients developed disease flare in the MTX group when remission had not been achieved upon IFX discontinuation, while only two of five (40.0%) patients did in the BUC + MTX group despite non-remission status upon IFX discontinuation (p = 0.053). Further, the state of remission significantly influenced the disease flare rate in the MTX group (91.7% and 40.0% in non-remission and remission patients, respectively; p = 0.014), although values were comparable between non-remission and remission patients in the BUC + MTX group (40.0% and 29.4%, respectively; p = 1.00), suggesting the effect of BUC on maintaining minimal disease activity.
Discussion
To our knowledge, this is the first clinical trial to examine the usefulness of non-biological DMARD combination therapy after disease control with biological agents. Approximately 50% reduction in incidence of disease flare after discontinuation of IFX was demonstrated by adding another DMARD, namely BUC, to MTX therapy, suggesting that DMARD combination therapy should be considered not only for remission induction before application of biological agents, but also for the maintenance of disease control after withdrawal of biological agents.
In a real-world clinical setting, remission due to treatment discontinuation of anti-TNF biological agents is generally only 2–6% [Citation21], although a recent observational cohort showed that IFX could be discontinued in 16% and down-titrated in 45% of RA patients [Citation22]. In this context, the RRR study was designed to evaluate the possibility of maintaining remission, or at least low disease activity, of RA in 114 patients with various disease durations (range: 0.1–38.0 years, mean: 5.9 years) [Citation8]. The flare rate at 1 year after discontinuation of IFX was 45% (n = 46) in patients for whom a DAS28-ESR < 3.2 was maintained for 24 weeks with IFX therapy. This flare rate was reproducible in the MTX group in the BuSHIDO trial, as 44.4% and 63.0% of patients at 1 and 2 years after discontinuation, respectively, showed disease flare.
In addition, the RRR study revealed that significantly more patients with DAS28 < 2.225 at study entry (IFX discontinuation) maintained DAS28 < 3.2 after 1 year than did those with DAS28 ≥ 2.225 at entry (71.4% versus 32.6%). Similarly, in the BuSHIDO trial, the DAS28-CRP value at IFX discontinuation was significantly greater in flare-positive patients than in flare-free ones for all patients as well as in the MTX group, but not in the BUC + MTX group. The addition of BUC at IFX discontinuation appeared to increase the critical threshold of disease activity status for clinical flare in conjunction with the results shown in .
Figure 4. Comparison of flare rates stratified by treatment groups and the achievement of remission by ACR/EULAR Boolean definition upon IFX discontinuation. *P = 0.014 versus Boolean remission (–) in the MTX group by Fisher's exact test.
Further, duration of combination treatment may influence disease suppression, as we noted a decreasing trend in instances of disease flare in BUC-continuing vs. BUC-discontinuing or MTX-alone patients. Previous BUC users without adverse events were 7 of 22 (31.8%) patients in the BUC + MTX group and 17 of 27 (63.0%) patients in the MTX group. The flare rate was comparable between previous BUC users and non-users in the BUC + MTX group (37.5% vs. 28.6%). After the disease flare, IFX was re-introduced for 10 and 3 patients, respectively, in the MTX group and the BUC + MTX group, which was successful in all the patients. MTX dose was increased in three patients and one patient, respectively, and BUC was added to MTX in one patient in the MTX group.
We have previously shown that BUC is similarly effective whether it is used before or after MTX [Citation9]. Further, therapeutic effects of the combination of MTX and BUC have been compared with each monotherapy in early RA patients [Citation10]. At 96 weeks, the ACR20 response rate was 79.2% in the BUC + MTX group, which was significantly higher than the rates of 45.8% for the BUC group and 43.5% for the MTX group. Given that BUC is a strongly recommended DMARD (grade A) according to the guideline for RA management from a national study group in Japan, this compound has been widely used as monotherapy or in combination with MTX or salazosulfapyridine [Citation23].
As for its safety profile, all adverse events observed in this study were non-serious and subsided upon BUC discontinuation. As previously reported [Citation9], rash was the most frequent adverse event within 3 months, while proteinuria developed around 6 months after BUC commencement. Yellowed fingernails and taste disturbance are other well-known adverse events [Citation24], although they were not reported in the present study.
Several limitations to the present study warrant mention, namely its small patient number, low dose of weekly MTX (8.3 ± 2.6 mg and 7.8 ± 1.4 mg in the BUC + MTX and MTX groups, respectively), and the current availability of BUC being limited mostly to Japan and South Korea, meaning it is a drug unfamiliar to people in other countries. Therefore, the future studies including other DMARDs than BUC, such as salazosulfapyridine, hydroxychloroquine and tacrolimus, will be warranted. While the officially approved maximum dose of MTX in Japan was raised from 8 to 16 mg/week starting in February 2011, that was more than 1 year after the completion of the patient enrollment in this study.
In conclusion, The BuSHIDO trial demonstrated that the addition of BUC to MTX reduced the flare rate for 2 years after IFX discontinuation due to remission or reduced disease activity sustained for > 6 months. These present findings suggest that DMARD combination therapy may be a preferable choice upon achieving good disease control by biological agents with respect to minimizing the risk of disease flare that occurs after the discontinuation of such agents. Further clinical trials using different DMARD combinations and biological agents should be considered to build upon these findings.
Acknowledgements
The authors gratefully acknowledge all relevant medical staffs in Saitama Medical Center and Keio University, especially Mrs. Harumi Kondo, for supporting data collection.
Conflict of interest
K Amano has received research grant support from and Astellas, Chugai and Pfizer and speaking honoraria from Abbott, Astellas, Bristol Myers, Chugai, Eizai, Mitsubishi-Tanabe and Pfizer.
T Takeuchi has received research grant support from and Abbott, Astellas, Bristol Myers, Chugai, Daiichi Sankyo, Eizai, Janssen, Mitsubishi-Tanabe, Nippon Shinyaku, Otsuka, Pfizer, Sanofi-aventis, Santen, Takeda, Teijin and speaking honoraria/consultancy fee from Abbott, Astellas, Asahi Kasei, Astra Zeneca, Bristol Myers, Chugai, Eizai, Eli-Lilly, Janssen, Johnson&Johnson, Mitsubishi-Tanabe, Pfizer and Symbio.
H Kameda has received research grant support from and Bristol Myers, Eizai and Pfizer and speaking honoraria/consultancy fee from Abbott, Chugai, Eizai, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Quintiles, Santen and UCB.
M Kishimoto is a full-time employee of Santen Pharmaceutical Co. Ltd.
References
- Goronzy JJ, Weyand CM. Developments in the scientific understanding of rheumatoid arthritis. Arthritis Res Ther. 2009;11(5):249.
- Smolen JS, Aletaha D, Bijlsma JWJ, Breedveld FC, Boumpas D, Burmester G, et al.;for the T2T Expert Committee: Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631–7.
- Kiely PD, Deighton C, Dixey J, Ostör AJ; British Society for Rheumatology Standards, Guidelines and Audit Working Group. Biologic agents for rheumatoid arthritis—negotiating the NICE technology appraisals. Rheumatology (Oxford). 2012;51(1):24–31.
- Quinn MA, Conaghan PG, O’Connor PJ, Karim Z, Greenstein A, Brown A, et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52(1):27–35.
- Goekoop-Ruiterman YPM, de Vries-Bouwsta JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Comparison of treatment strategies in early rheumatoid arthritis. A randomized trial. Ann Intern Med. 2007;146(6):406–15.
- Buch MH, Marzo-Ortega H, Bingham SJ, Emery P. Long-term treatment of rheumatoid arthritis with tumour necrosis factor α blockade: outcome of ceasing and restarting biological. Rheumatology (Oxford). 2004;43(2):243–4.
- Saleem B, Keen H, Goeb V, Parmar R, Nizam S, Hensor EM, et al. Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped?Ann Rheum Dis. 2010;69(9):1636–42.
- Tanaka Y, Takeuchi T, Mimori T, Saito K, Nawata M, Kameda H, et al.; RRR study investigators. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis. 2010;69(7):1286–91.
- Sekiguchi N, Kameda H, Amano K, Takeuchi T. Efficacy and safety of bucillamine, a D-penicillamine analogue, in patients with active rheumatoid arthritis. Mod Rheumatol. 2006;16(2):85–91.
- Ichikawa Y, Saito T, Yamanaka H, Akizuki M, Kondo H, Kobayashi S, et al.; MTX-BUC Combination Study Group; Japanese Ministry of Health, Labour and Welfare's “Research for Establishment of Therapeutic Guidelines in Early Rheumatoid Arthritis”. Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study. Mod Rheumatol. 2005;15(5):323–8.
- Eguchi K, Kawakami A, Ida H, Nakashima M, Yamashita I, Sakai M, et al. Bucillamine inhibits T cell adhesion to human endothelial cells. J Rheumatol. 1992;19(7):1045–50.
- Hashimoto K, Lipsky PE:Immunosuppression by the disease modifying antirheumatic drug bucillamine: Inhibition of human T lymphocyte function by bucillamine and its metabolites. J Rheumatol. 1993;20(6):953–7.
- Hirohata S, Lipsky PE. Comparative inhibitory effects of bucillamine and D-penicillamine on the function of human B cells and T cells. Arthritis Rheum. 1994;37(6):942–50.
- Matsuno H, Sugiyama E, Muraguchi A, Nezuka T, Kubo T, Matsuura K, Tsuji H. Pharmacological effects of SA96 (bucillamine) and its metabolites as immunomodulating drugs–the disulfide structure of SA-96 metabolites plays a critical role in the pharmacological action of the drug. Int J Immunopharmacol. 1998;20(6):295–304.
- Aono H, HasunumaT, Fujisawa K, Nakajima T, Yamamoto K, Mita S, Nishioka K. Direct suppression of human synovial cell proliferation in vitro by salazosulfapyridine and bucillamine. J Rheumatol. 1996; 23(1):65–70.
- Nagashima M, Wauke K, Hirano D, Ishigami S, Aono H, Takai M, et al. Effects of combinations of anti-rheumatic drugs on the production of vascular endothelial growth factor and basic fibroblast growth factor in cultured synoviocytes and patients with rheumatoid arthritis. Rheumatology (Oxford). 2000;39(11):1255–62.
- Inoue E, Yamanaka H, Hara M, Tomatsu T, Kamatani N. Comparison of disease activity score (DAS) 28-erythrocyte sedimentation rate and DAS28-C-reactive protein threshold values. Ann Rheum Dis. 2007;66(3):407–9.
- Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.
- van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 2000;27:261–3.
- Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al.; American College of Rheumatology; European League Against Rheumatism. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63: 573–86 and Ann Rheum Dis. 2011;70:404–13.
- Du Pan SM, Dehler S, Ciurea A, Ziswiler HR, Gabay C, Finckh A;Swiss Clinical Quality Management Physicians: Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis. Arthritis Care Res. 2009;61(5):560–8.
- van der Maas A, Kievit W, van den Bemt BJF, van den Hoogen FH, van Riel PL, den Broeder AA. Down-titration and discontinuation of infliximab in rheumatoid arthritis patients with stable low disease activity and stable treatment: an observational cohort study. Ann Rheum Dis. 2012;71(11):1849–54.
- Iwatani M, Inoue E, Nakamura T, Nakajima A, Hara M, Tomatsu T, Kamatani N, Yamanaka H. Efficacy profile of bucillamine in rheumatoid arthritis patients in a large observational cohort study, IORRA. Mod Rheumatol. 2006;16(6):376–80.
- Nakagomi D, Ikeda K, Kawashima H, Kobayashi Y, Suto A, Nakajima H. Bucillamine-induced yellow nail in Japanese patients with rheumatoid arthritis: two case reports and a review of 36 reported cases. Rheumatol Int. 2013;33(3):793–7 (Nov 17 2011 Epub ahead of print).