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Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?
AUTREV-01599; No of Pages 7 Autoimmunity Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug? Ennio Giulio Favalli a,⁎, Martina Biggioggero a,b, Pier Luigi Meroni a,b a b
Department of Rheumatology, Gaetano Pini Institute, Milan, Italy Department of Clinical Sciences and Community Health, University of Milan, Istituto Auxologico Italiano, Milan, Italy
a r t i c l e
i n f o
Article history: Received 18 May 2014 Accepted 28 May 2014 Available online xxxx
a b s t r a c t The improvement of rheumatoid arthritis (RA) management has been strictly related to methotrexate (MTX) long-term effectiveness, safety profile and its widespread use in clinical practice over the last decades. According to the results of several head-to-head comparative trials against other synthetic DMARDs, MTX has been recognised as the “anchor drug” for the treatment of RA at the end of the 1990s. The subsequent increasing knowledge in the area of RA pathophysiology has progressively expanded the arsenal of available therapeutic tools, especially by the introduction of novel drugs such as biological DMARDs. The introduction of therapies targeted to key molecules and cells involved in RA pathogenesis has significantly changed the strategies for disease management, possibly modifying the key role of MTX. This review first analyses data supporting the evolution of MTX towards the role of “anchor drug” for RA in the pre-biologic era. We will then examine how the introduction and progressive spreading of biological agents could have modified the central role of MTX in the approach to RA. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of MTX in the pre-biologic era . . . . . . . . . . . . . . . . . 2.1. MTX monotherapy vs other sDMARDs . . . . . . . . . . . . . . 2.1.1. MTX vs auranofin (AUR) . . . . . . . . . . . . . . . 2.1.2. MTX vs azathioprine (AZA) . . . . . . . . . . . . . . 2.1.3. MTX vs cyclosporine A (CSA) . . . . . . . . . . . . . 2.1.4. MTX vs intramuscular gold (gold sodium thiomalate [GST]) 2.1.5. MTX vs Leflunomide (LEF) . . . . . . . . . . . . . . . 2.1.6. MTX vs sulfasalazine (SSZ) . . . . . . . . . . . . . . 2.2. MTX in combination with other sDMARDs . . . . . . . . . . . . 3. The role of MTX in the biologic era . . . . . . . . . . . . . . . . . . 3.1. MTX as a gold-standard comparator for bDMARDs RCTs . . . . . . 3.2. MTX as a first line treatment in newly diagnosed RA . . . . . . . 3.3. MTX as a combination drug in association with bDMARDs . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1 . Introduction ⁎ Corresponding author at: Department of Rheumatology, Gaetano Pini Institute, Milan, Via Gaetano Pini, 9, 20122 Milan, Italy. Tel.: + 39 0258296624, + 39 3289659778 (Mobile); fax: +39 0258296315. E-mail address: [email protected] (E.G. Favalli).
The treatment of rheumatoid arthritis (RA) in the 20th century is characterised by a steady evolution of new agents and new approaches. For more than 50 years the treatment of RA has been
http://dx.doi.org/10.1016/j.autrev.2014.08.026 1568-9972/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026
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E.G. Favalli et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
based on corticosteroids, NSAIDs, and synthetic disease-modifying anti-rheumatic drugs (sDMARDs) such as gold salts, penicillamine, anti-malarials, and sulfasalazine. Methotrexate (MTX) was first introduced in rheumatology in 1962 for the treatment of psoriatic arthritis [1], based on the wrong assumption of a possible interference with the proliferation of connective tissues. MTX was approved as a therapy for active RA in 1988 after two placebo-controlled studies involving a total of 224 patients treated for a maximum of 24 weeks [2,3]. The mode of action of the drug in RA is not entirely clear yet, although the increase in adenosine levels and the reduction of pro-inflammatory cytokines seem to play a more predominant role than the inhibition of cellular proliferation [4]. Since the MTX introduction, much has changed in drug discovery and strategies for RA. In particular, over the 1990s two major advances may account for the improved status of RA patients. Firstly, a new approach considering RA as a “medical emergency”, which requires a shift in strategy from a “pyramid”, in which DMARDs were deferred for several years, to an earlier and more aggressive intervention with a goal of remission [5]. Secondly, the fact that MTX has been recognized as the DMARD with the most long-term effectiveness and safety, and the “anchor drug” for RA management before the introduction of biologic agents [6]. At the end of the century the identification of tumor necrosis factor (TNF) as a key player in the inflammatory and destructive pathways of the disease initiated a landmark shift of interest away from agents with poorly understood mechanisms of action towards therapies targeted to key molecules and cells involved in RA pathogenesis [7]. Advances in understanding of the role of T cells, B cells and cytokines such as IL-6 have paved the way to the development of additional biological drugs beyond TNF inhibitors (TNFi) [8], such as abatacept, rituximab and tocilizumab [9–13], all formally approved after randomised controlled trials (RCTs) conducted against MTX [14–21]. After more than ten years of experience, biological DMARDs (bDMARDs) have consistently shown good efficacy and safety in patients with RA [22–25] and are now widespread used in daily practice. In this review, we will first briefly summarise the data supporting the evolution of MTX towards the role of anchor drug for RA in the pre-biologic era. We will then examine how the introduction and progressive spreading of biological agents could have modified the central role of MTX in the management of RA. 2 . The role of MTX in the pre-biologic era The use of MTX for the treatment of RA in clinical practice was very limited at the end of the 1980s. Data from historical large RA cohorts showed a proportion of MTX RA treated patients lower than 10% between 1975 and 1988 [26–28]. The early reluctance in using MTX as
the initial DMARD may be explained by at least two reasons: a) rheumatologists were more familiar with traditional DMARDs; b) concerns about safety profile including hepatic and hematologic toxicities, as well as a possible predisposition to later malignancies. However, in the subsequent decades several RCTs head-to-head comparing MTX monotherapy with other available sDMARDs have been performed (Table 1), significantly modifying the role of MTX in daily practice. 2.1. MTX monotherapy vs other sDMARDs 2.1.1 . MTX vs auranofin (AUR) In a 36-week RCT in 281 patients with active RA treated with MTX or AUR, the clinical response (swollen joint count [SJC] and tender joint count [TJC]) with MTX occurred earlier and was consistently greater (P b 0.01) than with AUR. Adverse reactions were reported more frequently in the AUR group [29]. However, in a subsequent RCT involving 335 patients and comparing MTX, AUR and the combination of both, no statistically significant differences were found among the treatment groups in terms of clinical response and safety profiles, even if patients taking AUR alone had a slower onset of response than patients taking MTX alone [30]. 2.1.2 . MTX vs azathioprine (AZA) MTX was directly compared with AZA in two RCTs with similar results. In the first one, involving 64 patients randomly assigned to receive either AZA (100 mg daily) or oral MTX (7.5 mg weekly), both clinical response (SJC, erythrocyte sedimentation rate [ESR], C-reactive protein level [CRP], and Disease Activity Score [DAS]) at 24 and 48 week checkpoints [31] and radiographic progression [32] were significantly better in the MTX treated group, with a lower rate of serious adverse reactions. In the second study [33], 209 patients were randomised to receive escalating doses of MTX (5–15 mg/week), AZA (50–150 mg/day), or the combination of both. The proportion of responder patients was significantly higher in the MTX treated group compared with AZA (45% vs 26%, respectively) and a trend towards decreased radiologic progression was seen in MTX treated patients only. 2.1.3 . MTX vs cyclosporine A (CSA) Two RCTs comparing MTX with CSA showed different findings. Drosos et al. [34] demonstrated a similar clinical response (SJC, TJC, ESR, and CRP) and radiographic progression in two groups of early RA patients (disease duration b 3 years) randomly assigned to receive oral CSA (3 mg/kg/day) or oral MTX (0.15 mg/kg/week). More recently, an open RCT in 126 patients to MTX, CSA or SSZ reported a significantly higher American College of Rheumatology (ACR)50 response in MTX compared to CSA treated patients (57% vs 31%, respectively;
Table 1 Head-to-head with other synthetic DMARDs. Author [Ref]
Drugs
Weinblatt [29] Williams [30] Jeurissen [31,32] Willkens [33]
MTX vs AUR MTX vs AUR + MTX vs AUR MTX vs AZA MTX vs AZA + MTX vs AZA
Follow-up
Drosos [34] Ferraccioli [35] Hamilton [36]
MTX vs CSA MTX vs SSZ vs CSA MTX vs GST
104 weeks 24 weeks 48 weeks
51 vs 52 42 vs 42 vs 42 69 vs 72
Rau [37] Strand [38,40] Emery [41] Bao [42] Haagsma [43] Dougados [44] Capell [45]
MTX vs GST MTX vs Placebo vs LEF MTX vs LEF MTX vs LEF MTX vs SSZ + MTX vs SSZ MTX vs SSZ + MTX vs SSZ MTX vs SSZ + MTX vs SSZ
156 52 52 24 52 52 52
87 vs 87 182 vs 118 vs 182 498 vs 501 213 vs 291 35 vs 36 vs 34 68 vs 69 vs 68 56 vs 54 vs 55
36 48 48 48
weeks weeks weeks weeks
weeks weeks weeks weeks weeks weeks weeks
No. of patients
Results
142 vs 138 114 vs 106 vs 115 31 vs 33 67 vs 69 vs 73
MTX is more effective and better tolerated than AUR No differences between MTX and AUR MTX is more efficacious and more rapid than AZA MTX is more efficacious than AZA. Trend towards decrease radiographic progression only in MTX No differences in efficacy and radiographic progression MTX is more efficacious than CSA and SSZ GST and low dose MTX showed equivalent efficacy, but toxicity was more common in GST No differences in clinical efficacy and radiographic progression No differences in the efficacy of MTX vs LEF MTX is more efficacious than LEF, with low 2-year radiographic progression LEF is as effective but safer than MTX No differences in efficacy and radiographic progression between MTX and SSZ No differences in efficacy and radiographic progression between MTX and SSZ No differences in efficacy and radiographic progression between MTX and SSZ
MTX: methotrexate; LEF: leflunomide; SSZ; sulfasalazine; AZA: azathioprine; GST: gold sodium thiomalate; AUR: auranofin; CSA: cyclosporine A.
Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026
E.G. Favalli et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
P = 0.002) [35]. In both studies the proportion of adverse events (AEs) was similar in MTX and CSA treated groups. 2.1.4 . MTX vs intramuscular gold (gold sodium thiomalate [GST]) MTX showed a similar clinical response (ESR, CRP, Ritchie Articular Index, and pain score) and a significantly higher proportion of withdrawals for toxicity (19% MTX vs 43% GST, p = 0.0026) compared to GST in a 48 week head-to-head RCT [36]. It should be noticed that in this study MTX was used at relatively lower doses (median dose: 10 mg/weekly) than the optimal doses currently recommended. In a second double-blind RCT evaluating damage progression, 174 patients were assigned to receive weekly intramuscular injections of either 15 mg MTX or 50 mg GST for 3 years. No statistically significant difference in clinical efficacy and radiographic progression between the 2 treatment groups at all follow-up points was found [37]. 2.1.5 . MTX vs Leflunomide (LEF) As a part of the clinical development programme for LEF of the Leflunomide Rheumatoid Arthritis Investigators Groups, 482 patients were randomly assigned to LEF (100 mg daily on days 1–3, then 20 mg daily), placebo, or MTX (7.5 mg weekly, titrated progressively to 15 mg weekly over weeks 7). No statistically significant differences were found in the comparison of LEF and MTX treated patients regarding ACR20 response at 1 (52% vs 46%, respectively) [38] and 2-year follow-up (79% vs 67%, respectively) [39]. Moreover, radiographic progression at 1- and 2-year evaluation [38,39] and improvement in physical function and health related quality of life at 2-years [40] were similar in the two treatment groups. A direct comparison between MTX and LEF was performed in another RCT including 999 RA subjects randomised to MTX (10–15 mg/week) for 52 weeks or LEF (loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) [41]. After 1 year, improvement seen with MTX was significantly greater than that with LEF in terms of ACR20 response (64.8 vs 50.5%; P b 0.0001) and mean change from baseline of TJC (−9.7 vs −8.3; P = 0.006), SJC (−9.0 vs −6.8; P = 0.0001), physician global assessment (−1.2 vs −0.9; P b 0.001). Radiographic progression was similar with both treatment protocols at 1 year, whereas a significant difference in mean change from baseline of Larsen score in favour of MTX was found at 2 years. The proportion of AEs leading to withdrawal at 2 years (MTX 21%, LEF 27%) and the overall frequency of serious AEs (MTX 8%, LEF 7%) were comparable in both treatment groups. In a third comparative trial including 504 RA patients evaluated during a follow-up period of 24 weeks, LEF was found effective as MTX but with a better safety profile [42]. In particular, 62% patients in the LEF group met the ACR20 criteria versus 60% in the MTX one, and the incidence of AEs was significantly lower in LEF than in MTX treated patients (16.8% vs 28.1%; p = 0.002). 2.1.6 . MTX vs sulfasalazine (SSZ) A direct comparison of MTX with SSZ was performed in 3 RCTs [43–45] that divided the study population (105, 205, and 165 patients, respectively) into 3 treatment arms (SSZ alone [2000 to maximum 3000 mg daily], MTX alone [7.5 to maximum 25 mg weekly], and the combination of the two). In all these studies, no significant differences emerged in the 1-year head-to-head comparison between MTX and SSZ in terms of clinical efficacy (measured as DAS), radiographic progression (Total Sharp score), and frequency of AEs. On the contrary, in the previously mentioned study by Ferraccioli et al. [35] directly comparing MTX, CSA, and SSZ, the proportion of patients achieving ACR50 response at 12 months was significantly higher in the MTX than in the SSZ treated group (57% vs 33%, P b 0.01), with a similar safety profile. Overall, the results of these head-to-head comparative RCTs have strongly demonstrated the superiority of MTX compared with other sDMARDs, further supporting its long-term effectiveness, safety profile and use in more than 40% of RA patients between 1988 and 1998 [26–28]. Despite this widespread and long use, considerable variation
3
still exists among rheumatologists in prescribing MTX, particularly in the dosage and folic acid supplementation [46]. The dose of MTX as monotherapy can range from 7.5 to 25 mg/week, depending on national guidelines and physician's preference. Available literature has suggested that MTX toxicity is dose-dependent and low dose MTX monotherapy treatment in any case effective [47,48]. More recently, a systematic review of MTX monotherapy for RA has recommended initial treatment with 10–15 mg orally with dose increases to 20–30 mg/week if needed and tolerated [49]. 2.2. MTX in combination with other sDMARDs Since MTX alone may not fully control disease activity in all RA patients, between 1995 and 2005 a number of MTX and non-biologic DMARDs combination regimens have been suggested to convey superior efficacy in comparison with monotherapy. DMARDs association strategies have been evaluated in both sDMARDs-naïve (“step-down” approach) and refractory RA (“step-up” approach), with available results for CSA [50,51], LEF [52], SZP [43–45], GST [53], and hydroxychloroquine (HCQ) [54]. In 2008 a systematic review of the literature and meta-analysis about this topic, including a total of 19 trials (2025 patients), concluded that in DMARD-naïve patients the balance of efficacy/toxicity favours MTX monotherapy, whereas in DMARDs inadequate responders the evidence is still inconclusive [55]. These findings have been subsequently confirmed by Gaujoux-Viala et al. [56] in a systematic literature review informing the 2010 EULAR recommendations for the management of RA. Since then, additional studies suggested that sDMARDs combination may be superior to MTX monotherapy in both MTX-naïve and MTX insufficient responders. In the tREACH trial [57], 281 very early MTX-naïve patients with high probability of developing persistent arthritis according to the Visser model were randomised to receive MTX alone or in association with SSZ and HCQ. DAS after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy (0.39 (0.67 to 0.11, 95% CI)). In the TEAR trial [58] 755 RA patients who did not have an appropriate response to MTX were randomly assigned to 1 of 4 treatment arms: immediate treatment with MTX plus ETN, immediate oral triple therapy (MTX plus SSZ plus HCQ), or step-up from MTX monotherapy to one of the combination therapies (MTX plus ETN or MTX plus SSZ plus HCQ) at week 24 if the DAS28-ESR was N3.2. At week 24 patients in the 2 immediatetreatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P b 0.0001). According to the results of these studies, 2013 EULAR recommendations suggest the use of sDMARDs combination therapy as an appropriate alternative strategy alongside the use of MTX monotherapy [59]. 3 . The role of MTX in the biologic era At the moment of the introduction of bDMARDs for the treatment of RA, reports indicated a trend towards more widespread use of MTX by many rheumatologists as the primary “anchor drug” in patients with early RA [6]. After more than 15 years of experience with biologic drugs, the role of MTX in the treatment of RA has not been substantially changed. 3.1. MTX as a gold-standard comparator for bDMARDs RCTs Moving from the consolidate role of MTX as a gold-standard therapy for RA, most of the RCTs aiming to the approval of a new biologic agent for this indication have been designed as “step-up” or “add on” studies, in which patients were eligible only if they incompletely responded to MTX. The study population was enrolled to receive either MTX monotherapy or MTX in association with the tested biologic drug. Not surprisingly, not responsive patients displayed a greater efficacy to the addition
Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026
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E.G. Favalli et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
of a second drug versus the addition of a placebo. In fact, all the RCTs clearly demonstrated the superiority of combination therapy over MTX monotherapy, as reported in Table 2 [14–20]. This eventually led to the approval of TNF inhibitors, abatacept (ABT) and tocilizumab (TCZ) for the treatment of MTX poor responders. However, very few data on the direct comparison between bDMARD monotherapy and MTX have been published yet. In the TEMPO trial [14] 686 RA patients were randomised to receive oral MTX (up to 20 mg/ week), ETN (25 mg twice a week), or the combination of both, providing data on the direct comparison between bDMARD monotherapy and MTX. The combination therapy resulted significantly better than ETN and MTX mono-therapies in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression. Focusing on direct comparison between ETN and MTX groups, no statistically significant differences emerged in terms of 1-year clinical response (ACR20 76% vs 75%, ACR50 48% vs 43%, and ACR70 24% vs 19%, respectively), whereas 1-year damage worsening was significantly lower in the ETN group compared with MTX (proportion of patient without progression 68% vs 57%, respectively; P = 0.02. Mean modified total Sharp score (mTSS) change from baseline 0.52 vs 2.80, respectively; P = 0.04). This finding was confirmed by 2-year follow-up data, showing a significantly lower mean change from baseline in mTTS in patients receiving ETN compared with those receiving MTX (1.10 vs 3.34, respectively; P = 0.05) [60]. In the GO-FORWARD trial [18] 444 RA patients with insufficient response to MTX were randomised to receive MTX alone, golimumab (GLM) 100 mg alone, GLM 50 mg plus MTX or GLM 100 mg plus MTX. At 52 weeks, no significant differences emerged in the comparison of ACR20, ACR50 and ACR70 responses achieved in patients treated with a monotherapy regimen (MTX vs GLM 100 mg, 43.6% vs 45.1%, 27.8% vs 28.6%, and 15% vs 17.3%, respectively), despite the higher GLM dosage (100 mg) compared with the one currently approved for the treatment of RA (50 mg). Indeed, to date only the AMBITION study, a 6 month RCT including 673 patients with active RA for whom previous treatment with MTX had not failed, has been especially designed to head-to-head compare a bDMARD monotherapy with MTX [61]. Study population was randomly assigned either to TCZ 8 mg/kg every 4 weeks, or to MTX (starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks), with the proportion of patients achieving ACR20 response at week 24 as the primary endpoint. The intention-to-treat analysis demonstrated that TCZ monotherapy was better than MTX with higher ACR20 (69.9% vs 52.5%; p b 0.001), ACR50 (44.1% vs 33.5%; p = 0.002), and
ACR70 (28% vs 15.1%; p b 0.001) responses. Moreover, TCZ patients were five times more likely to achieve DAS28 remission (odds ratio vs MTX: 5.83; 95% confidence interval [CI] 3.27 to 10.40), and approximately four times more likely to achieve at least a moderate EULAR response (odds ratio vs MTX: 4.24, 95% CI 2.92 to 6.14). Overall, RCTs carried out in long-standing RA demonstrated that bDMARDs are superior to MTX only when used in association with MTX, but not when used alone. This would suggest a step-up approach with the introduction of bDMARDs only in MTX insufficient responders, as proposed by 2010 EULAR recommendations for the treatment of RA [62]. 3.2. MTX as a first line treatment in newly diagnosed RA After biologic drug approval for the treatment of MTX-IR RA patients, the research focused on an earlier use of biotherapies in the disease course. Thus, a number of RCTs evaluating bDMARDs in association with MTX compared with MTX alone in MTX-naïve patients were performed (Table 2) [63–69]. Once again, all these studies cannot be considered as head-to-head RCTs since they compared a combination therapy with a monotherapy regimen. As expected, the proportion of patients achieving a clinical remission was significantly higher and radiographic progression lower in groups treated with biologics compared to those with MTX only in all the considered RCTs. Only 2 of these studies included also a subgroup treated with a biologic drug alone, providing data on direct comparison with MTX monotherapy: the ERA study and the PREMIER study. The ERA study is a 24 month RCT with both clinical and radiographic primary endpoints, in which 632 MTX-naïve early RA patients were randomised to receive either twice-weekly subcutaneous etanercept (ETN, 10 or 25 mg) or weekly escalating doses of oral MTX (7.5– 20 mg/week) [65,70]. The patients in the group assigned to the higher ETN dose had significantly greater areas under the curve for the numeric index of the ACR response [ACR-N AUC] for 3, 6, 9, and 12 months than did the patients in the MTX group (P b 0.05). However, no differences in the proportion of patients achieving ACR20 (72% vs 65%; P = 0.16), 50, and 70 responses at 12 months were found by comparing ETN and MTX treated groups. The mean increase in the erosion score was significantly lower in the 25-mg ETN group than in the MTX group at both 6-month (0.30 vs 0.68; P = 0.001) and 12-month (0.47 vs 1.03; P = 0.002) evaluation, as well as the mean total modified Sharp score (mTSS) increase at 6 months (0.57 vs 1.06; P = 0.001), but not at 12 months (1.00 vs
Table 2 Randomised controlled studies of biologic drugs for RA. Study [Ref]
Drugs
No. of patients
ACR20 response, % (follow-up period)
P
Late RA AIM [19] AMBITION [61] ATTRACT [15] DE019 [16] GO-FORWARD [18] OPTION [20] RAPID1 [17] REFLEX [21] TEMPO [14]
MTX vs ABT + MTX MTX vs TCZ MTX vs IFX + MTX MTX vs ADA + MTX MTX vs GLM + MTX MTX vs TCZ + MTX MTX vs CZP + MTX MTX vs RTX + MTX MTX vs ETN + MTX vs ETN
219 vs 433 284 vs 288 88 vs 86 200 vs 207 133 vs 89 204 vs 205 199 vs 393 209 vs 308 228 vs 231 vs 223
39.7 vs 73.1 (52 weeks) 52.5 vs 69.9 (24 weeks) 17 vs 42 (54 weeks) 24 vs 59 (52 weeks) 27.8 vs 59.6 (24 weeks) 26 vs 59 (24 weeks) 13.6 vs 58.8 (24 weeks) 209 vs 308 (24 weeks) 75 vs 85 vs 76 (52 weeks)
b0.001 0.001 b0.001 b0.001 b0.001 b0.0001 b0.001 b0.0001 0.0091 (MTX vs combo) n.s. (MTX vs ETN)
Early RA AGREE [69] ASPIRE [66] COMET [64] ERA [65] GO-BEFORE [67] IMAGE [68] PREMIER [63]
MTX vs ABT + MTX MTX vs IFX + MTX MTX vs ETN + MTX MTX vs ETN 25 mg vs ETN 10 mg MTX vs GLM + MTX MTX vs RTX + MTX MTX vs ADA + MTX vs ADA
253 vs 256 282 vs 359 268 vs 274 217 vs 207 vs 208 160 vs 159 249 vs 250 257 vs 268 vs 274
42.3 vs 57.4 (52 weeks)* 53.6 vs 62.4 (54 weeks) 67 vs 86 (52 weeks) 65 vs 72 (52 weeks) 49.4 vs 61.6 (24 weeks) 64 vs 80 (52 weeks) 63 vs 73 vs 54 (52 weeks)
b0.001 0.028 b0.0001 0.16 0.028 b0.0001 b0.001 (MTX vs combo) 0.022 (MTX vs ADA)
ACR: American College of Rheumatology; RA: rheumatoid arthritis; MTX: methotrexate; ETN: etanercept; n.s.: not significant; TCZ: tocilizumab; IFX: infliximab; ADA: adalimumab; ABT: abatacept; RTX: rituximab; CZP: certolizumb pegol; GLM: golimumab; *ACR50 response, % (ACR20 not performed).
Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026
E.G. Favalli et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
1.59; P = 0.11) [65]. At 24 months, significantly more patients in the 25-mg ETN group achieved an ACR20 response than in the MTX group (72% versus 59%; P = 0.005) and the mean changes in mTSS and erosion score in the 25-mg ETN treated patients (1.3 and 0.66 units, respectively) were significantly lower than those in the MTX group (3.2 and 1.86 units, respectively; P b 0.001) (70). The PREMIER study [63] was designed by randomising 799 early MTX-naïve RA patients into 3 treatment arms (oral MTX 20 mg/week, adalimumab [ADA] 40 mg/every other week, or the combination of both). Co-primary endpoints at year 1 were ACR50 improvement and the mean change from baseline in the mTTS. Similarly to what was previously reported in the TEMPO trial, combination therapy was superior to both ADA and MTX mono-therapies in all clinical and radiographic outcomes, whereas the proportion of 12 and 24-month ACR20 (54% vs 63% and 49% vs 56%, respectively), ACR50 (41% vs 46% and 37% vs 43%, respectively), and ACR70 (26% vs 28% and 28% vs 28%, respectively) responses was comparable between ADA and MTX groups. Otherwise, damage progression at both 1 and 2 year evaluations was significantly lower in ADA treated patients directly compared with MTX treated ones (mean change from baseline in mTTS 3.0 vs 5.7 and 5.5 vs 10.4, respectively; P b 0.001). Based on overall findings from RCTs conducted in MTX-naïve populations, bDMARDs, both alone or in combination with MTX, conferred a significant structural benefit in comparison with MTX in early disease. However, despite the evidence of this benefit, more recent data coming from GUEPARD [71] and TEAR [58] trials suggested that early bDMARDs use may not be more effective in patients with early RA than starting MTX first and adding a biological agent to MTX rapidly if active disease prevails. Because of these concerns, 2010 EULAR recommendations for RA management [62] reserved the early use of bDMARDs before MTX only in exceptional patients with particular unfavourable prognostic signs, and more recently 2013 update [59] strongly discouraged the use of bDMARDs before trying a MTX approach. 3.3. MTX as a combination drug in association with bDMARDs As described in previous sections, the efficacy of bDMARDs in combination with MTX is well established and appears to be the most effective regimen currently available for patients with early or established RA who have failed to respond to traditional DMARDs. Data from the main RCTs with TNF inhibitors, rituximab, and abatacept consistently showed the superiority of the MTX plus bDMARD combination rather than bDMARD monotherapy. A weekly dose of 10 mg MTX or more appeared to be effective and appropriate for use with ADA and, until proven otherwise, also with all other TNF inhibitors. This statement was supported by data coming from the CONCERTO trial [72], in which 395 early MTX-naïve RA patients were randomised to open-label ADA plus weekly blinded 2.5, 5, 10 or 20 mg MTX. At 26 weeks, statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose, but with minimal differences comparing 10 and 20 mg MTX. Only TCZ has been repeatedly demonstrated to be superior as a monotherapy over MTX, firstly in the previously mentioned AMBITION trial [61], and more recently in the ACT-RAY trial [73], in which 556 MTX insufficient responder patients were randomly assigned either to continue MTX with the addition of TCZ or switch to TCZ alone. No significant differences were found in both 24 week DAS-ESR remission rate (40.4% for TCZ + MTX and 34.8% for TCZ alone [p = 0.19]) and 2-year radiographic progression (Genant–Sharp score progression ≤ smallest detectable change in 91% and 87% of patients, respectively), confirming no clinically relevant superiority of the TCZ + MTX add-on over the switch to TCZ monotherapy strategy. However, most recently, additional data became available, albeit only in abstract form, revealing that only in combination with MTX TCZ showed consistent significant superiority over MTX with regard to clinical, functional and structural outcomes [74].
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Thus, 2013 EULAR recommendations stated that, if biological monotherapy must be initiated, TCZ has some supportive evidence, but taken together, the available data strongly support the use of all biological agents in combination with MTX rather than in monotherapy [59]. However, biologic monotherapy is commonly used in clinical practice. A survey of RA prescribing practices found that 28–30% of patients with newly diagnosed RA received a bDMARD as monotherapy [75], as well as data coming from European National Registries showed that more than 30% RA patients are treated with a biologic drug alone [76,77]. 4 . Conclusions In conclusion, MTX had progressively become the “anchor drug” for RA management during the pre-biologic era because of its long-term effectiveness and safety profile confirmed in several head-to-head comparative RCTs against other sDMARDs. Despite the introduction of biotherapies targeted to key molecules and cells involved in RA pathogenesis, MTX maintained its key role in the management of RA over the last two decades. Take-home messages • As gold-standard comparator for all biologic drug RCTs, MTX showed a lower efficacy compared with the association bDMARDs plus MTX, but a similar efficacy to bDMARDs monotherapy. • MTX is still indicated as the first line therapy to treat newly diagnosed RA, both alone or in combination with other sDMARDs. • International recommendations strongly encourage the use of bDMARDs in association with MTX rather than in monotherapy.
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Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug? Ennio Giulio Favalli a,⁎, Martina Biggioggero a,b, Pier Luigi Meroni a,b a b
Department of Rheumatology, Gaetano Pini Institute, Milan, Italy Department of Clinical Sciences and Community Health, University of Milan, Istituto Auxologico Italiano, Milan, Italy
a r t i c l e
i n f o
Article history: Received 18 May 2014 Accepted 28 May 2014 Available online xxxx
a b s t r a c t The improvement of rheumatoid arthritis (RA) management has been strictly related to methotrexate (MTX) long-term effectiveness, safety profile and its widespread use in clinical practice over the last decades. According to the results of several head-to-head comparative trials against other synthetic DMARDs, MTX has been recognised as the “anchor drug” for the treatment of RA at the end of the 1990s. The subsequent increasing knowledge in the area of RA pathophysiology has progressively expanded the arsenal of available therapeutic tools, especially by the introduction of novel drugs such as biological DMARDs. The introduction of therapies targeted to key molecules and cells involved in RA pathogenesis has significantly changed the strategies for disease management, possibly modifying the key role of MTX. This review first analyses data supporting the evolution of MTX towards the role of “anchor drug” for RA in the pre-biologic era. We will then examine how the introduction and progressive spreading of biological agents could have modified the central role of MTX in the approach to RA. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of MTX in the pre-biologic era . . . . . . . . . . . . . . . . . 2.1. MTX monotherapy vs other sDMARDs . . . . . . . . . . . . . . 2.1.1. MTX vs auranofin (AUR) . . . . . . . . . . . . . . . 2.1.2. MTX vs azathioprine (AZA) . . . . . . . . . . . . . . 2.1.3. MTX vs cyclosporine A (CSA) . . . . . . . . . . . . . 2.1.4. MTX vs intramuscular gold (gold sodium thiomalate [GST]) 2.1.5. MTX vs Leflunomide (LEF) . . . . . . . . . . . . . . . 2.1.6. MTX vs sulfasalazine (SSZ) . . . . . . . . . . . . . . 2.2. MTX in combination with other sDMARDs . . . . . . . . . . . . 3. The role of MTX in the biologic era . . . . . . . . . . . . . . . . . . 3.1. MTX as a gold-standard comparator for bDMARDs RCTs . . . . . . 3.2. MTX as a first line treatment in newly diagnosed RA . . . . . . . 3.3. MTX as a combination drug in association with bDMARDs . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1 . Introduction ⁎ Corresponding author at: Department of Rheumatology, Gaetano Pini Institute, Milan, Via Gaetano Pini, 9, 20122 Milan, Italy. Tel.: + 39 0258296624, + 39 3289659778 (Mobile); fax: +39 0258296315. E-mail address: [email protected] (E.G. Favalli).
The treatment of rheumatoid arthritis (RA) in the 20th century is characterised by a steady evolution of new agents and new approaches. For more than 50 years the treatment of RA has been
http://dx.doi.org/10.1016/j.autrev.2014.08.026 1568-9972/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026
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based on corticosteroids, NSAIDs, and synthetic disease-modifying anti-rheumatic drugs (sDMARDs) such as gold salts, penicillamine, anti-malarials, and sulfasalazine. Methotrexate (MTX) was first introduced in rheumatology in 1962 for the treatment of psoriatic arthritis [1], based on the wrong assumption of a possible interference with the proliferation of connective tissues. MTX was approved as a therapy for active RA in 1988 after two placebo-controlled studies involving a total of 224 patients treated for a maximum of 24 weeks [2,3]. The mode of action of the drug in RA is not entirely clear yet, although the increase in adenosine levels and the reduction of pro-inflammatory cytokines seem to play a more predominant role than the inhibition of cellular proliferation [4]. Since the MTX introduction, much has changed in drug discovery and strategies for RA. In particular, over the 1990s two major advances may account for the improved status of RA patients. Firstly, a new approach considering RA as a “medical emergency”, which requires a shift in strategy from a “pyramid”, in which DMARDs were deferred for several years, to an earlier and more aggressive intervention with a goal of remission [5]. Secondly, the fact that MTX has been recognized as the DMARD with the most long-term effectiveness and safety, and the “anchor drug” for RA management before the introduction of biologic agents [6]. At the end of the century the identification of tumor necrosis factor (TNF) as a key player in the inflammatory and destructive pathways of the disease initiated a landmark shift of interest away from agents with poorly understood mechanisms of action towards therapies targeted to key molecules and cells involved in RA pathogenesis [7]. Advances in understanding of the role of T cells, B cells and cytokines such as IL-6 have paved the way to the development of additional biological drugs beyond TNF inhibitors (TNFi) [8], such as abatacept, rituximab and tocilizumab [9–13], all formally approved after randomised controlled trials (RCTs) conducted against MTX [14–21]. After more than ten years of experience, biological DMARDs (bDMARDs) have consistently shown good efficacy and safety in patients with RA [22–25] and are now widespread used in daily practice. In this review, we will first briefly summarise the data supporting the evolution of MTX towards the role of anchor drug for RA in the pre-biologic era. We will then examine how the introduction and progressive spreading of biological agents could have modified the central role of MTX in the management of RA. 2 . The role of MTX in the pre-biologic era The use of MTX for the treatment of RA in clinical practice was very limited at the end of the 1980s. Data from historical large RA cohorts showed a proportion of MTX RA treated patients lower than 10% between 1975 and 1988 [26–28]. The early reluctance in using MTX as
the initial DMARD may be explained by at least two reasons: a) rheumatologists were more familiar with traditional DMARDs; b) concerns about safety profile including hepatic and hematologic toxicities, as well as a possible predisposition to later malignancies. However, in the subsequent decades several RCTs head-to-head comparing MTX monotherapy with other available sDMARDs have been performed (Table 1), significantly modifying the role of MTX in daily practice. 2.1. MTX monotherapy vs other sDMARDs 2.1.1 . MTX vs auranofin (AUR) In a 36-week RCT in 281 patients with active RA treated with MTX or AUR, the clinical response (swollen joint count [SJC] and tender joint count [TJC]) with MTX occurred earlier and was consistently greater (P b 0.01) than with AUR. Adverse reactions were reported more frequently in the AUR group [29]. However, in a subsequent RCT involving 335 patients and comparing MTX, AUR and the combination of both, no statistically significant differences were found among the treatment groups in terms of clinical response and safety profiles, even if patients taking AUR alone had a slower onset of response than patients taking MTX alone [30]. 2.1.2 . MTX vs azathioprine (AZA) MTX was directly compared with AZA in two RCTs with similar results. In the first one, involving 64 patients randomly assigned to receive either AZA (100 mg daily) or oral MTX (7.5 mg weekly), both clinical response (SJC, erythrocyte sedimentation rate [ESR], C-reactive protein level [CRP], and Disease Activity Score [DAS]) at 24 and 48 week checkpoints [31] and radiographic progression [32] were significantly better in the MTX treated group, with a lower rate of serious adverse reactions. In the second study [33], 209 patients were randomised to receive escalating doses of MTX (5–15 mg/week), AZA (50–150 mg/day), or the combination of both. The proportion of responder patients was significantly higher in the MTX treated group compared with AZA (45% vs 26%, respectively) and a trend towards decreased radiologic progression was seen in MTX treated patients only. 2.1.3 . MTX vs cyclosporine A (CSA) Two RCTs comparing MTX with CSA showed different findings. Drosos et al. [34] demonstrated a similar clinical response (SJC, TJC, ESR, and CRP) and radiographic progression in two groups of early RA patients (disease duration b 3 years) randomly assigned to receive oral CSA (3 mg/kg/day) or oral MTX (0.15 mg/kg/week). More recently, an open RCT in 126 patients to MTX, CSA or SSZ reported a significantly higher American College of Rheumatology (ACR)50 response in MTX compared to CSA treated patients (57% vs 31%, respectively;
Table 1 Head-to-head with other synthetic DMARDs. Author [Ref]
Drugs
Weinblatt [29] Williams [30] Jeurissen [31,32] Willkens [33]
MTX vs AUR MTX vs AUR + MTX vs AUR MTX vs AZA MTX vs AZA + MTX vs AZA
Follow-up
Drosos [34] Ferraccioli [35] Hamilton [36]
MTX vs CSA MTX vs SSZ vs CSA MTX vs GST
104 weeks 24 weeks 48 weeks
51 vs 52 42 vs 42 vs 42 69 vs 72
Rau [37] Strand [38,40] Emery [41] Bao [42] Haagsma [43] Dougados [44] Capell [45]
MTX vs GST MTX vs Placebo vs LEF MTX vs LEF MTX vs LEF MTX vs SSZ + MTX vs SSZ MTX vs SSZ + MTX vs SSZ MTX vs SSZ + MTX vs SSZ
156 52 52 24 52 52 52
87 vs 87 182 vs 118 vs 182 498 vs 501 213 vs 291 35 vs 36 vs 34 68 vs 69 vs 68 56 vs 54 vs 55
36 48 48 48
weeks weeks weeks weeks
weeks weeks weeks weeks weeks weeks weeks
No. of patients
Results
142 vs 138 114 vs 106 vs 115 31 vs 33 67 vs 69 vs 73
MTX is more effective and better tolerated than AUR No differences between MTX and AUR MTX is more efficacious and more rapid than AZA MTX is more efficacious than AZA. Trend towards decrease radiographic progression only in MTX No differences in efficacy and radiographic progression MTX is more efficacious than CSA and SSZ GST and low dose MTX showed equivalent efficacy, but toxicity was more common in GST No differences in clinical efficacy and radiographic progression No differences in the efficacy of MTX vs LEF MTX is more efficacious than LEF, with low 2-year radiographic progression LEF is as effective but safer than MTX No differences in efficacy and radiographic progression between MTX and SSZ No differences in efficacy and radiographic progression between MTX and SSZ No differences in efficacy and radiographic progression between MTX and SSZ
MTX: methotrexate; LEF: leflunomide; SSZ; sulfasalazine; AZA: azathioprine; GST: gold sodium thiomalate; AUR: auranofin; CSA: cyclosporine A.
Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026
E.G. Favalli et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
P = 0.002) [35]. In both studies the proportion of adverse events (AEs) was similar in MTX and CSA treated groups. 2.1.4 . MTX vs intramuscular gold (gold sodium thiomalate [GST]) MTX showed a similar clinical response (ESR, CRP, Ritchie Articular Index, and pain score) and a significantly higher proportion of withdrawals for toxicity (19% MTX vs 43% GST, p = 0.0026) compared to GST in a 48 week head-to-head RCT [36]. It should be noticed that in this study MTX was used at relatively lower doses (median dose: 10 mg/weekly) than the optimal doses currently recommended. In a second double-blind RCT evaluating damage progression, 174 patients were assigned to receive weekly intramuscular injections of either 15 mg MTX or 50 mg GST for 3 years. No statistically significant difference in clinical efficacy and radiographic progression between the 2 treatment groups at all follow-up points was found [37]. 2.1.5 . MTX vs Leflunomide (LEF) As a part of the clinical development programme for LEF of the Leflunomide Rheumatoid Arthritis Investigators Groups, 482 patients were randomly assigned to LEF (100 mg daily on days 1–3, then 20 mg daily), placebo, or MTX (7.5 mg weekly, titrated progressively to 15 mg weekly over weeks 7). No statistically significant differences were found in the comparison of LEF and MTX treated patients regarding ACR20 response at 1 (52% vs 46%, respectively) [38] and 2-year follow-up (79% vs 67%, respectively) [39]. Moreover, radiographic progression at 1- and 2-year evaluation [38,39] and improvement in physical function and health related quality of life at 2-years [40] were similar in the two treatment groups. A direct comparison between MTX and LEF was performed in another RCT including 999 RA subjects randomised to MTX (10–15 mg/week) for 52 weeks or LEF (loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) [41]. After 1 year, improvement seen with MTX was significantly greater than that with LEF in terms of ACR20 response (64.8 vs 50.5%; P b 0.0001) and mean change from baseline of TJC (−9.7 vs −8.3; P = 0.006), SJC (−9.0 vs −6.8; P = 0.0001), physician global assessment (−1.2 vs −0.9; P b 0.001). Radiographic progression was similar with both treatment protocols at 1 year, whereas a significant difference in mean change from baseline of Larsen score in favour of MTX was found at 2 years. The proportion of AEs leading to withdrawal at 2 years (MTX 21%, LEF 27%) and the overall frequency of serious AEs (MTX 8%, LEF 7%) were comparable in both treatment groups. In a third comparative trial including 504 RA patients evaluated during a follow-up period of 24 weeks, LEF was found effective as MTX but with a better safety profile [42]. In particular, 62% patients in the LEF group met the ACR20 criteria versus 60% in the MTX one, and the incidence of AEs was significantly lower in LEF than in MTX treated patients (16.8% vs 28.1%; p = 0.002). 2.1.6 . MTX vs sulfasalazine (SSZ) A direct comparison of MTX with SSZ was performed in 3 RCTs [43–45] that divided the study population (105, 205, and 165 patients, respectively) into 3 treatment arms (SSZ alone [2000 to maximum 3000 mg daily], MTX alone [7.5 to maximum 25 mg weekly], and the combination of the two). In all these studies, no significant differences emerged in the 1-year head-to-head comparison between MTX and SSZ in terms of clinical efficacy (measured as DAS), radiographic progression (Total Sharp score), and frequency of AEs. On the contrary, in the previously mentioned study by Ferraccioli et al. [35] directly comparing MTX, CSA, and SSZ, the proportion of patients achieving ACR50 response at 12 months was significantly higher in the MTX than in the SSZ treated group (57% vs 33%, P b 0.01), with a similar safety profile. Overall, the results of these head-to-head comparative RCTs have strongly demonstrated the superiority of MTX compared with other sDMARDs, further supporting its long-term effectiveness, safety profile and use in more than 40% of RA patients between 1988 and 1998 [26–28]. Despite this widespread and long use, considerable variation
3
still exists among rheumatologists in prescribing MTX, particularly in the dosage and folic acid supplementation [46]. The dose of MTX as monotherapy can range from 7.5 to 25 mg/week, depending on national guidelines and physician's preference. Available literature has suggested that MTX toxicity is dose-dependent and low dose MTX monotherapy treatment in any case effective [47,48]. More recently, a systematic review of MTX monotherapy for RA has recommended initial treatment with 10–15 mg orally with dose increases to 20–30 mg/week if needed and tolerated [49]. 2.2. MTX in combination with other sDMARDs Since MTX alone may not fully control disease activity in all RA patients, between 1995 and 2005 a number of MTX and non-biologic DMARDs combination regimens have been suggested to convey superior efficacy in comparison with monotherapy. DMARDs association strategies have been evaluated in both sDMARDs-naïve (“step-down” approach) and refractory RA (“step-up” approach), with available results for CSA [50,51], LEF [52], SZP [43–45], GST [53], and hydroxychloroquine (HCQ) [54]. In 2008 a systematic review of the literature and meta-analysis about this topic, including a total of 19 trials (2025 patients), concluded that in DMARD-naïve patients the balance of efficacy/toxicity favours MTX monotherapy, whereas in DMARDs inadequate responders the evidence is still inconclusive [55]. These findings have been subsequently confirmed by Gaujoux-Viala et al. [56] in a systematic literature review informing the 2010 EULAR recommendations for the management of RA. Since then, additional studies suggested that sDMARDs combination may be superior to MTX monotherapy in both MTX-naïve and MTX insufficient responders. In the tREACH trial [57], 281 very early MTX-naïve patients with high probability of developing persistent arthritis according to the Visser model were randomised to receive MTX alone or in association with SSZ and HCQ. DAS after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy (0.39 (0.67 to 0.11, 95% CI)). In the TEAR trial [58] 755 RA patients who did not have an appropriate response to MTX were randomly assigned to 1 of 4 treatment arms: immediate treatment with MTX plus ETN, immediate oral triple therapy (MTX plus SSZ plus HCQ), or step-up from MTX monotherapy to one of the combination therapies (MTX plus ETN or MTX plus SSZ plus HCQ) at week 24 if the DAS28-ESR was N3.2. At week 24 patients in the 2 immediatetreatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P b 0.0001). According to the results of these studies, 2013 EULAR recommendations suggest the use of sDMARDs combination therapy as an appropriate alternative strategy alongside the use of MTX monotherapy [59]. 3 . The role of MTX in the biologic era At the moment of the introduction of bDMARDs for the treatment of RA, reports indicated a trend towards more widespread use of MTX by many rheumatologists as the primary “anchor drug” in patients with early RA [6]. After more than 15 years of experience with biologic drugs, the role of MTX in the treatment of RA has not been substantially changed. 3.1. MTX as a gold-standard comparator for bDMARDs RCTs Moving from the consolidate role of MTX as a gold-standard therapy for RA, most of the RCTs aiming to the approval of a new biologic agent for this indication have been designed as “step-up” or “add on” studies, in which patients were eligible only if they incompletely responded to MTX. The study population was enrolled to receive either MTX monotherapy or MTX in association with the tested biologic drug. Not surprisingly, not responsive patients displayed a greater efficacy to the addition
Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026
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of a second drug versus the addition of a placebo. In fact, all the RCTs clearly demonstrated the superiority of combination therapy over MTX monotherapy, as reported in Table 2 [14–20]. This eventually led to the approval of TNF inhibitors, abatacept (ABT) and tocilizumab (TCZ) for the treatment of MTX poor responders. However, very few data on the direct comparison between bDMARD monotherapy and MTX have been published yet. In the TEMPO trial [14] 686 RA patients were randomised to receive oral MTX (up to 20 mg/ week), ETN (25 mg twice a week), or the combination of both, providing data on the direct comparison between bDMARD monotherapy and MTX. The combination therapy resulted significantly better than ETN and MTX mono-therapies in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression. Focusing on direct comparison between ETN and MTX groups, no statistically significant differences emerged in terms of 1-year clinical response (ACR20 76% vs 75%, ACR50 48% vs 43%, and ACR70 24% vs 19%, respectively), whereas 1-year damage worsening was significantly lower in the ETN group compared with MTX (proportion of patient without progression 68% vs 57%, respectively; P = 0.02. Mean modified total Sharp score (mTSS) change from baseline 0.52 vs 2.80, respectively; P = 0.04). This finding was confirmed by 2-year follow-up data, showing a significantly lower mean change from baseline in mTTS in patients receiving ETN compared with those receiving MTX (1.10 vs 3.34, respectively; P = 0.05) [60]. In the GO-FORWARD trial [18] 444 RA patients with insufficient response to MTX were randomised to receive MTX alone, golimumab (GLM) 100 mg alone, GLM 50 mg plus MTX or GLM 100 mg plus MTX. At 52 weeks, no significant differences emerged in the comparison of ACR20, ACR50 and ACR70 responses achieved in patients treated with a monotherapy regimen (MTX vs GLM 100 mg, 43.6% vs 45.1%, 27.8% vs 28.6%, and 15% vs 17.3%, respectively), despite the higher GLM dosage (100 mg) compared with the one currently approved for the treatment of RA (50 mg). Indeed, to date only the AMBITION study, a 6 month RCT including 673 patients with active RA for whom previous treatment with MTX had not failed, has been especially designed to head-to-head compare a bDMARD monotherapy with MTX [61]. Study population was randomly assigned either to TCZ 8 mg/kg every 4 weeks, or to MTX (starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks), with the proportion of patients achieving ACR20 response at week 24 as the primary endpoint. The intention-to-treat analysis demonstrated that TCZ monotherapy was better than MTX with higher ACR20 (69.9% vs 52.5%; p b 0.001), ACR50 (44.1% vs 33.5%; p = 0.002), and
ACR70 (28% vs 15.1%; p b 0.001) responses. Moreover, TCZ patients were five times more likely to achieve DAS28 remission (odds ratio vs MTX: 5.83; 95% confidence interval [CI] 3.27 to 10.40), and approximately four times more likely to achieve at least a moderate EULAR response (odds ratio vs MTX: 4.24, 95% CI 2.92 to 6.14). Overall, RCTs carried out in long-standing RA demonstrated that bDMARDs are superior to MTX only when used in association with MTX, but not when used alone. This would suggest a step-up approach with the introduction of bDMARDs only in MTX insufficient responders, as proposed by 2010 EULAR recommendations for the treatment of RA [62]. 3.2. MTX as a first line treatment in newly diagnosed RA After biologic drug approval for the treatment of MTX-IR RA patients, the research focused on an earlier use of biotherapies in the disease course. Thus, a number of RCTs evaluating bDMARDs in association with MTX compared with MTX alone in MTX-naïve patients were performed (Table 2) [63–69]. Once again, all these studies cannot be considered as head-to-head RCTs since they compared a combination therapy with a monotherapy regimen. As expected, the proportion of patients achieving a clinical remission was significantly higher and radiographic progression lower in groups treated with biologics compared to those with MTX only in all the considered RCTs. Only 2 of these studies included also a subgroup treated with a biologic drug alone, providing data on direct comparison with MTX monotherapy: the ERA study and the PREMIER study. The ERA study is a 24 month RCT with both clinical and radiographic primary endpoints, in which 632 MTX-naïve early RA patients were randomised to receive either twice-weekly subcutaneous etanercept (ETN, 10 or 25 mg) or weekly escalating doses of oral MTX (7.5– 20 mg/week) [65,70]. The patients in the group assigned to the higher ETN dose had significantly greater areas under the curve for the numeric index of the ACR response [ACR-N AUC] for 3, 6, 9, and 12 months than did the patients in the MTX group (P b 0.05). However, no differences in the proportion of patients achieving ACR20 (72% vs 65%; P = 0.16), 50, and 70 responses at 12 months were found by comparing ETN and MTX treated groups. The mean increase in the erosion score was significantly lower in the 25-mg ETN group than in the MTX group at both 6-month (0.30 vs 0.68; P = 0.001) and 12-month (0.47 vs 1.03; P = 0.002) evaluation, as well as the mean total modified Sharp score (mTSS) increase at 6 months (0.57 vs 1.06; P = 0.001), but not at 12 months (1.00 vs
Table 2 Randomised controlled studies of biologic drugs for RA. Study [Ref]
Drugs
No. of patients
ACR20 response, % (follow-up period)
P
Late RA AIM [19] AMBITION [61] ATTRACT [15] DE019 [16] GO-FORWARD [18] OPTION [20] RAPID1 [17] REFLEX [21] TEMPO [14]
MTX vs ABT + MTX MTX vs TCZ MTX vs IFX + MTX MTX vs ADA + MTX MTX vs GLM + MTX MTX vs TCZ + MTX MTX vs CZP + MTX MTX vs RTX + MTX MTX vs ETN + MTX vs ETN
219 vs 433 284 vs 288 88 vs 86 200 vs 207 133 vs 89 204 vs 205 199 vs 393 209 vs 308 228 vs 231 vs 223
39.7 vs 73.1 (52 weeks) 52.5 vs 69.9 (24 weeks) 17 vs 42 (54 weeks) 24 vs 59 (52 weeks) 27.8 vs 59.6 (24 weeks) 26 vs 59 (24 weeks) 13.6 vs 58.8 (24 weeks) 209 vs 308 (24 weeks) 75 vs 85 vs 76 (52 weeks)
b0.001 0.001 b0.001 b0.001 b0.001 b0.0001 b0.001 b0.0001 0.0091 (MTX vs combo) n.s. (MTX vs ETN)
Early RA AGREE [69] ASPIRE [66] COMET [64] ERA [65] GO-BEFORE [67] IMAGE [68] PREMIER [63]
MTX vs ABT + MTX MTX vs IFX + MTX MTX vs ETN + MTX MTX vs ETN 25 mg vs ETN 10 mg MTX vs GLM + MTX MTX vs RTX + MTX MTX vs ADA + MTX vs ADA
253 vs 256 282 vs 359 268 vs 274 217 vs 207 vs 208 160 vs 159 249 vs 250 257 vs 268 vs 274
42.3 vs 57.4 (52 weeks)* 53.6 vs 62.4 (54 weeks) 67 vs 86 (52 weeks) 65 vs 72 (52 weeks) 49.4 vs 61.6 (24 weeks) 64 vs 80 (52 weeks) 63 vs 73 vs 54 (52 weeks)
b0.001 0.028 b0.0001 0.16 0.028 b0.0001 b0.001 (MTX vs combo) 0.022 (MTX vs ADA)
ACR: American College of Rheumatology; RA: rheumatoid arthritis; MTX: methotrexate; ETN: etanercept; n.s.: not significant; TCZ: tocilizumab; IFX: infliximab; ADA: adalimumab; ABT: abatacept; RTX: rituximab; CZP: certolizumb pegol; GLM: golimumab; *ACR50 response, % (ACR20 not performed).
Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026
E.G. Favalli et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
1.59; P = 0.11) [65]. At 24 months, significantly more patients in the 25-mg ETN group achieved an ACR20 response than in the MTX group (72% versus 59%; P = 0.005) and the mean changes in mTSS and erosion score in the 25-mg ETN treated patients (1.3 and 0.66 units, respectively) were significantly lower than those in the MTX group (3.2 and 1.86 units, respectively; P b 0.001) (70). The PREMIER study [63] was designed by randomising 799 early MTX-naïve RA patients into 3 treatment arms (oral MTX 20 mg/week, adalimumab [ADA] 40 mg/every other week, or the combination of both). Co-primary endpoints at year 1 were ACR50 improvement and the mean change from baseline in the mTTS. Similarly to what was previously reported in the TEMPO trial, combination therapy was superior to both ADA and MTX mono-therapies in all clinical and radiographic outcomes, whereas the proportion of 12 and 24-month ACR20 (54% vs 63% and 49% vs 56%, respectively), ACR50 (41% vs 46% and 37% vs 43%, respectively), and ACR70 (26% vs 28% and 28% vs 28%, respectively) responses was comparable between ADA and MTX groups. Otherwise, damage progression at both 1 and 2 year evaluations was significantly lower in ADA treated patients directly compared with MTX treated ones (mean change from baseline in mTTS 3.0 vs 5.7 and 5.5 vs 10.4, respectively; P b 0.001). Based on overall findings from RCTs conducted in MTX-naïve populations, bDMARDs, both alone or in combination with MTX, conferred a significant structural benefit in comparison with MTX in early disease. However, despite the evidence of this benefit, more recent data coming from GUEPARD [71] and TEAR [58] trials suggested that early bDMARDs use may not be more effective in patients with early RA than starting MTX first and adding a biological agent to MTX rapidly if active disease prevails. Because of these concerns, 2010 EULAR recommendations for RA management [62] reserved the early use of bDMARDs before MTX only in exceptional patients with particular unfavourable prognostic signs, and more recently 2013 update [59] strongly discouraged the use of bDMARDs before trying a MTX approach. 3.3. MTX as a combination drug in association with bDMARDs As described in previous sections, the efficacy of bDMARDs in combination with MTX is well established and appears to be the most effective regimen currently available for patients with early or established RA who have failed to respond to traditional DMARDs. Data from the main RCTs with TNF inhibitors, rituximab, and abatacept consistently showed the superiority of the MTX plus bDMARD combination rather than bDMARD monotherapy. A weekly dose of 10 mg MTX or more appeared to be effective and appropriate for use with ADA and, until proven otherwise, also with all other TNF inhibitors. This statement was supported by data coming from the CONCERTO trial [72], in which 395 early MTX-naïve RA patients were randomised to open-label ADA plus weekly blinded 2.5, 5, 10 or 20 mg MTX. At 26 weeks, statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose, but with minimal differences comparing 10 and 20 mg MTX. Only TCZ has been repeatedly demonstrated to be superior as a monotherapy over MTX, firstly in the previously mentioned AMBITION trial [61], and more recently in the ACT-RAY trial [73], in which 556 MTX insufficient responder patients were randomly assigned either to continue MTX with the addition of TCZ or switch to TCZ alone. No significant differences were found in both 24 week DAS-ESR remission rate (40.4% for TCZ + MTX and 34.8% for TCZ alone [p = 0.19]) and 2-year radiographic progression (Genant–Sharp score progression ≤ smallest detectable change in 91% and 87% of patients, respectively), confirming no clinically relevant superiority of the TCZ + MTX add-on over the switch to TCZ monotherapy strategy. However, most recently, additional data became available, albeit only in abstract form, revealing that only in combination with MTX TCZ showed consistent significant superiority over MTX with regard to clinical, functional and structural outcomes [74].
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Thus, 2013 EULAR recommendations stated that, if biological monotherapy must be initiated, TCZ has some supportive evidence, but taken together, the available data strongly support the use of all biological agents in combination with MTX rather than in monotherapy [59]. However, biologic monotherapy is commonly used in clinical practice. A survey of RA prescribing practices found that 28–30% of patients with newly diagnosed RA received a bDMARD as monotherapy [75], as well as data coming from European National Registries showed that more than 30% RA patients are treated with a biologic drug alone [76,77]. 4 . Conclusions In conclusion, MTX had progressively become the “anchor drug” for RA management during the pre-biologic era because of its long-term effectiveness and safety profile confirmed in several head-to-head comparative RCTs against other sDMARDs. Despite the introduction of biotherapies targeted to key molecules and cells involved in RA pathogenesis, MTX maintained its key role in the management of RA over the last two decades. Take-home messages • As gold-standard comparator for all biologic drug RCTs, MTX showed a lower efficacy compared with the association bDMARDs plus MTX, but a similar efficacy to bDMARDs monotherapy. • MTX is still indicated as the first line therapy to treat newly diagnosed RA, both alone or in combination with other sDMARDs. • International recommendations strongly encourage the use of bDMARDs in association with MTX rather than in monotherapy.
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Please cite this article as: Favalli EG, et al, Methotrexate for the treatment of rheumatoid arthritis in the biologic era: Still an “anchor” drug?, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.08.026