Expert Review of Clinical Pharmacology
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20
Combination therapy for early rheumatoid arthritis: a treatment holiday perspective Shintaro Hirata & Yoshiya Tanaka To cite this article: Shintaro Hirata & Yoshiya Tanaka (2015) Combination therapy for early rheumatoid arthritis: a treatment holiday perspective, Expert Review of Clinical Pharmacology, 8:1, 115-122, DOI: 10.1586/17512433.2015.984689 To link to this article: http://dx.doi.org/10.1586/17512433.2015.984689
Published online: 25 Nov 2014.
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Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierj20 Download by: [Australian Catholic University]
Date: 19 September 2017, At: 21:31
Review
Combination therapy for early rheumatoid arthritis: a treatment holiday perspective Downloaded by [Australian Catholic University] at 21:31 19 September 2017
Expert Rev. Clin. Pharmacol. 8(1), 115–122 (2015)
Shintaro Hirata and Yoshiya Tanaka* The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu, 807-8555, Japan *Author for correspondence: Tel.: +81 936 031 611 Fax: +81 936 919 334 [email protected]
To date, the significance of early intervention with methotrexate and biological disease-modifying anti-rheumatic drugs for rheumatoid arthritis (RA) has not been realized. Longitudinal safety and cost have arisen as new concerns. The concept of a treatment holiday, drug discontinuation after achieving remission, may solve these problems. The authors performed a systematic literature review and identified 13 reports from 10 studies (TNF20, BeSt, OPITMA, HIT-HARD, IMPROVED, PRIZE, IDEA, EMPIRE, tREACH and AVERT) for early RA (£2 years). Eight out of 13 reports (61.5%) were published in 2013 or 2014, indicating emerging interest in recent years. Also, the authors performed a sub-analysis of the HONOR study (n = 51) to compare early (£2 years) and established RA. The proportions of remission (REM) and low disease activity were higher in early RA (REM: 63.0 vs 33.3%, p = 0.0346; low disease activity: 77.8 vs 45.8%, p = 0.0185). In conclusion, early intervention is beneficial for successful treatment holiday, which may lead to risk and cost reduction. However, further investigation is required. KEYWORDS: disease-modifying anti-rheumatic drug • drug-free remission • early intervention • rheumatoid arthritis • treatment holiday
Combination therapy with synthetic & biological disease-modifying anti-rheumatic drug for patients with early rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-standing inflammatory disease characterized by polyarthritis as well as extra-articular manifestations, and subsequent joint destruction, leading to disability and shortening of lifetime [1]. RA also disturbs the quality of life through economic loss due to work impairment, as well as discomfort due to pain, fatigue or disability [2]. Thus, successful treatment against RA is significant for both individual as well as socio-economical aspects [2]. Recent advance in therapeutics against RA revolutionarily improved clinical outcomes including symptomatic, radiographic and functional aspects. The first step of new era in the treatment for RA began with methotrexate (MTX), followed by biological products such as TNF inhibitors, anti-IL-6R antibodies or cytotoxic T-lymphocyte-associated protein 4 immunoglobulin. These drugs are now referred to as
informahealthcare.com
10.1586/17512433.2015.984689
conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biological DMARDs (bDMARDs), respectively [3]. Especially, combination of bDMARDs and concomitant MTX has been found to be the most reliable treatment strategy to date, making clinical remission as a realistic target to treat [4]. In parallel, the significance of early intervention, a concept of ‘window of opportunity’, has been suggested [5]. Significance of treatment holiday in RA
However, new problems have arisen by the clinical application of bDMARDs: safety and financial concern. Long-term safety of bDMARDs with or without concomitant MTX is still an unsolved question, especially with regard to opportunistic infection and oncogenesis. Exploitation and production of bDMARDs require huge amount of money, resulting in very high pharmaceutical prices. To solve these new problems, information on how to withdraw drugs after successful induction of clinical remission, and how to maintain the stable status even after withdrawal of drugs,
2015 Informa UK Ltd
ISSN 1751-2433
115
Review
Hirata & Tanaka
has been highly anticipated in rheumatology society now [6]. Several investigators have shown possible successful drug withdrawal, the so-called ‘treatment holiday’ [7]. In addition, recent update of the European League against Rheumatism recommendations for the management of RA initially referred to withdrawal of bDMARDs after persistent remission [8]. Systematic literature review of treatment holiday for patients with early RA
Downloaded by [Australian Catholic University] at 21:31 19 September 2017
The authors performed a search of PubMed on July 5, 2014, using a systematic literature search strategy as below: 1. Rheumatoid arthritis 2. Discontinuation OR discontinuing OR stop OR stopping OR cessation OR withdrawal 3. Biological dMARDs OR biological drugs OR anti-TNF OR TNF inhibitor OR infliximab OR remicade OR etanercept OR enbrel OR adalimumab OR humira OR tocilizumab OR actemra OR roactemra OR abatacept OR orencia OR golimumab OR simponi OR certolizumab OR cimzia OR rituximab OR rituxan 4. Remission OR low disease activity 5. English [Language] 6. Arthritis, juvenile rheumatoid [MeSH] 7. Review [Filter] 8. #1 AND #2 AND #3 AND #4 AND #5 NOT #6 NOT #7 On performing a PubMed search on October 5, 2014, 88 original research articles were identified. Then systematic literature review revealed that 19 articles were candidate studies, and 69 articles were excluded. During screening the titles and abstracts of the citations and retrieved relevant articles, the following selection criteria were used: clinical trials of bDMARDs in patients with RA, followed by discontinuation of the bDMARDs due to preferable effectiveness but not due to adverse events or insufficient efficacy; patients of age >18 years with RA; data available on one or more of the following prespecified outcomes: ratio of remission or low disease activity (LDA) after at least 12 weeks of discontinuation and/or ratio of re-administration of the bDMARDs; and published after 1998 that the first bDMARD to be available. The reasons for exclusion were categorized into three groups: no description of discontinuing bDMARDs, reasons for discontinuing bDMARDs are not specified and no description of discontinuing bDMARDs due to preferable effectiveness. The authors also conducted the abstracts search on the American College of Rheumatology 2011, 2012, 2013, the European League against Rheumatism 2012, 2013, 2014 by the same policy, and finally identified 29 reports in total as the candidates. Among the 29 reports, 13 reports from 10 studies (TNF20 [9], Behandelstrategiee¨n [BeSt] [10–13], OPITMA [14], HIT-HARD [15], IMPROVED [16], PRIZE [17], IDEA [Infliximab as induction therapy in Early rheumatoid Arthritis] [18], EMPIRE [Etanercept and Methotrexate in Patients to Induce Remission in Early Arthritis] [19], tREACH [Rotterdam Early 116
Arthritis CoHort] [20] and AVERT [Assessing Very Early Rheumatoid arthritis Treatment] [21]) were identified as investigations of patients with early RA (defined as mean or median disease duration within 2 years) and are summarized in TABLE 1. Evidences of drug holiday for patients with early RA
bDMARD-free treatment in RA patients was first reported by a TNF20 study [9]. Patients with early RA who had less than 12 months of symptoms were treated with a combination of infliximab and MTX. One year after stopping the induction therapy, response was sustained in 70% of patients who received infliximab and MTX. A significant reduction in magnetic resonance imaging evidence of synovitis and erosions at 1 year was also observed. The BeSt study was conducted to compare four treatment strategies and to observe the clinical outcomes in patients with early RA (disease duration less than 2 years after onset, mean disease duration 0.8 years) [22]. In the BeSt study, 508 patients with high disease activity were distributed into four groups and were evaluated by disease activity score for 44 joints (DAS44) every 3 months. If DAS44 was >2.4 (intermediate or high disease activity), change or addition of medications was required; if DAS44) was £2.4 (remission or LDA), current medication was continued and if DAS44 £2.4 continued over 6 months, concomitant medications including infliximab were reduced and/or discontinued. In the fourth group of patients who were started on infliximab, 90 patients of 120 (75%) achieved LDA and infliximab was withdrawn in 77 cases because they maintained LDA for 6 months. The LDA was maintained in 43/77 patients (56%) for at least 1 year. Furthermore, more than half of the patients who discontinued infliximab successfully maintained LDA for more than 8 years, according to the 8-year follow-up of infliximab-free survival in patients with early RA [10–13]. A multinational, double-blinded, randomized controlled study was performed to determine the optimal protocol for treatment initiation with adalimumab plus MTX in patients with RA (OPTIMA) [14]. In this study, the withdrawal of adalimumab in early RA patients (with a mean RA duration of 3.9 months) was also assessed. Outcomes of withdrawal or continuation of adalimumab were assessed in patients who achieved a stable LDA target after 26 weeks of initially assigned treatment with adalimumab and MTX. Of the 466 RA patients treated with adalimumab and MTX, 207 (44%) achieved the stable LDA measured by disease activity score for 28 joints (C-reactive protein) (DAS28 [CRP]) at weeks 22 and 26 and were re-randomized to placebo (PBO) plus MTX or adalimumab plus MTX during the second study period for 52 weeks. After 52 weeks, 91 and 86% of patients who continued adalimumab treatment maintained LDA and remission, respectively, compared with 81 and 66% of patients who withdrew from adalimumab treatment. In the HIT-HARD study, the withdrawal of adalimumab in patients with early RA (mean RA duration: 1.7 months) was also assessed to find whether an early induction therapy with subsequent step-down strategy leads to a long-term clinical effect in early RA patients, as compared to initial and Expert Rev. Clin. Pharmacol. 8(1), (2015)
3.9 months (mean)
17 months (median)
MTX up to 25 mg
MTX
BeSt study arms
BeSt study arms
MTX 15 mg sc.
MTX
MTX
Infliximab
Infliximab
Last DMARD Including pts after cessation of IFX
Infliximab
Adalimumab
Adalimumab
Adalimumab (after failing to achieve DAS
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20
Combination therapy for early rheumatoid arthritis: a treatment holiday perspective Shintaro Hirata & Yoshiya Tanaka To cite this article: Shintaro Hirata & Yoshiya Tanaka (2015) Combination therapy for early rheumatoid arthritis: a treatment holiday perspective, Expert Review of Clinical Pharmacology, 8:1, 115-122, DOI: 10.1586/17512433.2015.984689 To link to this article: http://dx.doi.org/10.1586/17512433.2015.984689
Published online: 25 Nov 2014.
Submit your article to this journal
Article views: 148
View related articles
View Crossmark data
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierj20 Download by: [Australian Catholic University]
Date: 19 September 2017, At: 21:31
Review
Combination therapy for early rheumatoid arthritis: a treatment holiday perspective Downloaded by [Australian Catholic University] at 21:31 19 September 2017
Expert Rev. Clin. Pharmacol. 8(1), 115–122 (2015)
Shintaro Hirata and Yoshiya Tanaka* The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu, 807-8555, Japan *Author for correspondence: Tel.: +81 936 031 611 Fax: +81 936 919 334 [email protected]
To date, the significance of early intervention with methotrexate and biological disease-modifying anti-rheumatic drugs for rheumatoid arthritis (RA) has not been realized. Longitudinal safety and cost have arisen as new concerns. The concept of a treatment holiday, drug discontinuation after achieving remission, may solve these problems. The authors performed a systematic literature review and identified 13 reports from 10 studies (TNF20, BeSt, OPITMA, HIT-HARD, IMPROVED, PRIZE, IDEA, EMPIRE, tREACH and AVERT) for early RA (£2 years). Eight out of 13 reports (61.5%) were published in 2013 or 2014, indicating emerging interest in recent years. Also, the authors performed a sub-analysis of the HONOR study (n = 51) to compare early (£2 years) and established RA. The proportions of remission (REM) and low disease activity were higher in early RA (REM: 63.0 vs 33.3%, p = 0.0346; low disease activity: 77.8 vs 45.8%, p = 0.0185). In conclusion, early intervention is beneficial for successful treatment holiday, which may lead to risk and cost reduction. However, further investigation is required. KEYWORDS: disease-modifying anti-rheumatic drug • drug-free remission • early intervention • rheumatoid arthritis • treatment holiday
Combination therapy with synthetic & biological disease-modifying anti-rheumatic drug for patients with early rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-standing inflammatory disease characterized by polyarthritis as well as extra-articular manifestations, and subsequent joint destruction, leading to disability and shortening of lifetime [1]. RA also disturbs the quality of life through economic loss due to work impairment, as well as discomfort due to pain, fatigue or disability [2]. Thus, successful treatment against RA is significant for both individual as well as socio-economical aspects [2]. Recent advance in therapeutics against RA revolutionarily improved clinical outcomes including symptomatic, radiographic and functional aspects. The first step of new era in the treatment for RA began with methotrexate (MTX), followed by biological products such as TNF inhibitors, anti-IL-6R antibodies or cytotoxic T-lymphocyte-associated protein 4 immunoglobulin. These drugs are now referred to as
informahealthcare.com
10.1586/17512433.2015.984689
conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biological DMARDs (bDMARDs), respectively [3]. Especially, combination of bDMARDs and concomitant MTX has been found to be the most reliable treatment strategy to date, making clinical remission as a realistic target to treat [4]. In parallel, the significance of early intervention, a concept of ‘window of opportunity’, has been suggested [5]. Significance of treatment holiday in RA
However, new problems have arisen by the clinical application of bDMARDs: safety and financial concern. Long-term safety of bDMARDs with or without concomitant MTX is still an unsolved question, especially with regard to opportunistic infection and oncogenesis. Exploitation and production of bDMARDs require huge amount of money, resulting in very high pharmaceutical prices. To solve these new problems, information on how to withdraw drugs after successful induction of clinical remission, and how to maintain the stable status even after withdrawal of drugs,
2015 Informa UK Ltd
ISSN 1751-2433
115
Review
Hirata & Tanaka
has been highly anticipated in rheumatology society now [6]. Several investigators have shown possible successful drug withdrawal, the so-called ‘treatment holiday’ [7]. In addition, recent update of the European League against Rheumatism recommendations for the management of RA initially referred to withdrawal of bDMARDs after persistent remission [8]. Systematic literature review of treatment holiday for patients with early RA
Downloaded by [Australian Catholic University] at 21:31 19 September 2017
The authors performed a search of PubMed on July 5, 2014, using a systematic literature search strategy as below: 1. Rheumatoid arthritis 2. Discontinuation OR discontinuing OR stop OR stopping OR cessation OR withdrawal 3. Biological dMARDs OR biological drugs OR anti-TNF OR TNF inhibitor OR infliximab OR remicade OR etanercept OR enbrel OR adalimumab OR humira OR tocilizumab OR actemra OR roactemra OR abatacept OR orencia OR golimumab OR simponi OR certolizumab OR cimzia OR rituximab OR rituxan 4. Remission OR low disease activity 5. English [Language] 6. Arthritis, juvenile rheumatoid [MeSH] 7. Review [Filter] 8. #1 AND #2 AND #3 AND #4 AND #5 NOT #6 NOT #7 On performing a PubMed search on October 5, 2014, 88 original research articles were identified. Then systematic literature review revealed that 19 articles were candidate studies, and 69 articles were excluded. During screening the titles and abstracts of the citations and retrieved relevant articles, the following selection criteria were used: clinical trials of bDMARDs in patients with RA, followed by discontinuation of the bDMARDs due to preferable effectiveness but not due to adverse events or insufficient efficacy; patients of age >18 years with RA; data available on one or more of the following prespecified outcomes: ratio of remission or low disease activity (LDA) after at least 12 weeks of discontinuation and/or ratio of re-administration of the bDMARDs; and published after 1998 that the first bDMARD to be available. The reasons for exclusion were categorized into three groups: no description of discontinuing bDMARDs, reasons for discontinuing bDMARDs are not specified and no description of discontinuing bDMARDs due to preferable effectiveness. The authors also conducted the abstracts search on the American College of Rheumatology 2011, 2012, 2013, the European League against Rheumatism 2012, 2013, 2014 by the same policy, and finally identified 29 reports in total as the candidates. Among the 29 reports, 13 reports from 10 studies (TNF20 [9], Behandelstrategiee¨n [BeSt] [10–13], OPITMA [14], HIT-HARD [15], IMPROVED [16], PRIZE [17], IDEA [Infliximab as induction therapy in Early rheumatoid Arthritis] [18], EMPIRE [Etanercept and Methotrexate in Patients to Induce Remission in Early Arthritis] [19], tREACH [Rotterdam Early 116
Arthritis CoHort] [20] and AVERT [Assessing Very Early Rheumatoid arthritis Treatment] [21]) were identified as investigations of patients with early RA (defined as mean or median disease duration within 2 years) and are summarized in TABLE 1. Evidences of drug holiday for patients with early RA
bDMARD-free treatment in RA patients was first reported by a TNF20 study [9]. Patients with early RA who had less than 12 months of symptoms were treated with a combination of infliximab and MTX. One year after stopping the induction therapy, response was sustained in 70% of patients who received infliximab and MTX. A significant reduction in magnetic resonance imaging evidence of synovitis and erosions at 1 year was also observed. The BeSt study was conducted to compare four treatment strategies and to observe the clinical outcomes in patients with early RA (disease duration less than 2 years after onset, mean disease duration 0.8 years) [22]. In the BeSt study, 508 patients with high disease activity were distributed into four groups and were evaluated by disease activity score for 44 joints (DAS44) every 3 months. If DAS44 was >2.4 (intermediate or high disease activity), change or addition of medications was required; if DAS44) was £2.4 (remission or LDA), current medication was continued and if DAS44 £2.4 continued over 6 months, concomitant medications including infliximab were reduced and/or discontinued. In the fourth group of patients who were started on infliximab, 90 patients of 120 (75%) achieved LDA and infliximab was withdrawn in 77 cases because they maintained LDA for 6 months. The LDA was maintained in 43/77 patients (56%) for at least 1 year. Furthermore, more than half of the patients who discontinued infliximab successfully maintained LDA for more than 8 years, according to the 8-year follow-up of infliximab-free survival in patients with early RA [10–13]. A multinational, double-blinded, randomized controlled study was performed to determine the optimal protocol for treatment initiation with adalimumab plus MTX in patients with RA (OPTIMA) [14]. In this study, the withdrawal of adalimumab in early RA patients (with a mean RA duration of 3.9 months) was also assessed. Outcomes of withdrawal or continuation of adalimumab were assessed in patients who achieved a stable LDA target after 26 weeks of initially assigned treatment with adalimumab and MTX. Of the 466 RA patients treated with adalimumab and MTX, 207 (44%) achieved the stable LDA measured by disease activity score for 28 joints (C-reactive protein) (DAS28 [CRP]) at weeks 22 and 26 and were re-randomized to placebo (PBO) plus MTX or adalimumab plus MTX during the second study period for 52 weeks. After 52 weeks, 91 and 86% of patients who continued adalimumab treatment maintained LDA and remission, respectively, compared with 81 and 66% of patients who withdrew from adalimumab treatment. In the HIT-HARD study, the withdrawal of adalimumab in patients with early RA (mean RA duration: 1.7 months) was also assessed to find whether an early induction therapy with subsequent step-down strategy leads to a long-term clinical effect in early RA patients, as compared to initial and Expert Rev. Clin. Pharmacol. 8(1), (2015)
3.9 months (mean)
17 months (median)
MTX up to 25 mg
MTX
BeSt study arms
BeSt study arms
MTX 15 mg sc.
MTX
MTX
Infliximab
Infliximab
Last DMARD Including pts after cessation of IFX
Infliximab
Adalimumab
Adalimumab
Adalimumab (after failing to achieve DAS
