The consensus statement has been developed using nominal group and Delphi techniques, along with a systematic literature review (SLR). The project was carried out following the Declaration of Helsinki ethical principles for medical research involving human subjects, and in accordance with the Good Clinical Practice regulations. First, a group of 11rheumatologists (2 of them the coordinators) with interest and demonstrated experience in the management of RA were designated (Fig. 1).

Fig. 1.

Project development.

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The coordinators defined 13 questions (Table 1), connected to the use of MTX in combination with b- or tsDMARDs, that included the indication of the combination therapy, MTX dose, route of administration, dose adjustments, etc. A comprehensive SLR was performed to address these questions. The following PICO queries and inclusion criteria were defined: (1) Adult RA patients (population); (2) on, or considering the start of combined therapy with MTX and b-or tsDMARDs approved for RA including 5 tumor necrosis factor (TNF) inhibitors (infliximab, adalimumab, etanercept, golimumab, certolizumab pegol), abatacept (ABT), rituximab (RTX), interleukin 6 (IL-6) inhibitors tocilizumab and sarilumab, biosimilars, and Janus kinase inhibitors (JAKs) tofacitinib and baricitinib (intervention); (3) compared with placebo or an active drug (comparator); reporting efficacy and/or safety variables like composite activity indexes, radiographic progression, serious adverse events, etc. (outcomes); (4) searches were restricted to SLR and meta-analysis based on randomized controlled trials (RCTs) (study design), humans, and articles written in English and/or Spanish. The publications were identified by sensitive search strategies in the main bibliographic databases. For this purpose, an expert librarian designed the search strategies, using Mesh and text word terms. The following bibliographic databases were screened up to January 2019: Medline, Embase and the Cochrane Library. The abstracts of the two previous (2017 and 2018) annual scientific meetings of the American College of Rheumatology (ACR) and EULAR were also examined along with national and international consensus and guidelines. Two reviewers selected the articles and collected data, independently. Subsequently, a manual search of the bibliography of the articles that were finally included was performed. The quality was evaluated with the Oxford Center for Evidence Based Medicine recommendations.5 Subsequently, the coordinators proposed a set of preliminary recommendations based on the SLR results.

The experts held a nominal meeting in which objectives, scope and users were defined. Then, through guided discussions, the results of the SLR and the preliminary recommendations were analyzed. Afterwards, definitive recommendations were generated.

Recommendations were submitted to a Delphi process. All experts voted ‘yes’ or ‘no’ for every recommendation. Agreement was defined when at least 80% of experts voted ‘yes’. This high cut-off was established because the coordinators wanted to achieve a maximum level of agreement among the experts (when possible). Recommendations with a grade of agreement (GA) inferior to 80% were reassessed and, if appropriate, re-edited and voted on in a second round.

After the Delphi, and along with the results of the SLR, the final document was written. For each recommendation, the level of evidence (LE) and grade of recommendation (GR) were assigned according to the recommendations of the Oxford Center for Evidence Based Medicine recommendations.5

The SLR retrieved 530 articles (see Fig. 2). After the selection processes and the hand search 61 studies were finally included.

Fig. 2.

Studies flow-chart.

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Recommendations, evidence and expert's considerations

A total of 9 preliminary recommendations were proposed: 2 were not voted and were explained in the main text of the document and 3 new ones were generated. Finally, 10 recommendations were voted and accepted. The level of agreement was very high in all of them and was achieved in the first Delphi round. Table 2 depicts the recommendations with their respective LE, GR and GA.

In patients with established RA (but also in early RA) and inadequate response to MTX, different SLR and meta-analyses have shown6,7 that the addition of TNF inhibitors to MTX was superior to the biologics monotherapy in terms of disease activity (ACR20, 50, 70 response), function evaluated with the Health Assessment Questionnaire (HAQ), pain control, patient global assessment or radiographic progression. Although less evaluated (at least in RCTs), the combination of ABT or RTX plus MTX, compared with ABT or RTX monotherapy seems to be more effective as well.8–10

RCTs and observational studies have compared TCZ+MTX combination therapy with TCZ monotherapy in patients with inadequate response to MTX.11,12 Most of them have revealed no statistical differences between groups in outcomes such as pain, function, ACR response or Clinical Disease Activity Index and Simple Disease Activity Index remission rates, especially in the short term. However, in other trials, combined therapy was significantly superior in the ACR/EULAR Boolean remission rate or radiographic progression in the medium/long term.12–14 Similar results have been observed with other IL-6 inhibitors.15

The panel weighed up this heterogeneity and established that, in general, MTX (excluding contraindications) should not be discontinued because there is evidence that supports combination efficacy, especially in the long term. However, there might be cases in which IL-6 inhibitor monotherapy might be a good option (e.g. in case of MTX intolerance), but these cases should be carefully individualized.

Although data from RCTs have shown no efficacy differences between tofacitinib (TFC) monotherapy and combination therapy with MTX, a network meta-analysis depicted greater ACR20/50/70 responses with the drugs combination.6 However, due to the study design, these results should be considered cautiously. Moreover, it has been estimated that in absolute terms, 6 (0–12) extra patients out of 100 patients treated with TFC will achieve the ACR50 goal due to concomitant MTX therapy.7

Other SLRs and RCTs have revealed that the ACR response rates are similar when comparing patients on baricitinib (BARI) and MTX combination therapy with BARI monotherapy. However, in patients with no or limited prior DMARD treatment, the change in total Sharp score was significantly higher than MTX monotherapy only when BARI was combined with MTX, not for BARI monotherapy.11,16

As in the case of IL-6 inhibitors, with the evidence collected so far, the panel doesn’t recommend MTX cessation when considering the combination with tsDMARDs, especially with BARI.

A SLR that addressed MTX doses in biologic trials (most of them in MTX-inadequate responders), as well as other RCTs,17,18 have showed that the maximal MTX doses at the start of the bDMARDs combination were 25mg/week for oral and 15mg/week for parenteral routes, respectively. However, mean MTX doses were frequently around 12.5-15mg/week in these trials.18 In the same way, observational studies have described that maximum MTX doses when combined with bDMARDs are variable and reach up to 25–30mg/week, but mean doses are quite similar to the reported in the RCTs.19 In a randomized controlled trial (MUSICA) analyzing the efficacy of two doses of MTX (7.5mg vs 20mg, orally and/or injectable) in patients with established RA with an insufficient response to MTX (>15mg/week) who started adalimumab, the non-inferiority of the low dose was not met, although some clinical and ultrasound parameters do not reach statistical significance.19

The panel also kept in mind current guidelines in the management of RA.1–4 They recommend maximization of treatment effects that includes reaching an optimal MTX dose within a few weeks and maintaining the maximal dose (25–30mg weekly) for at least 8 weeks if tolerated. The panel supports these recommendations and therefore assumes that in patients with inadequate response to MTX in whom a bDMARD is considered, the maximum tolerated dose should have already been achieved irrespectively of the route of administration. This is the dose and route of administration that should be continued.

It has been stated that in established RA patients with inadequate response to MTX, MTX at 10mg/week provides additional efficacy to TNF inhibitors (including the reduction of the incidence of antidrug antibodies), while intolerance leading to discontinuation at these low doses was very rare.20 In the randomized trial CONCERTO in MTX naïve RA patients who started adalimumab, efficacy of 10 and 20mg/week MTX appeared equivalent.20 As exposed in the recommendation 4, it is possible that a bDMARD or tsDMARDs is indicated in a patient on MTX below 10mg/week due to toxicity/tolerability. In this cases the previous doses should be continued.

MTX doses when adding TFC in MTX inadequate responders are different among RCTs, from7.5 to 25mg/week.21,22 In the ORAL Standard trial, patients were receiving weekly 7.5–25mg MTX,23 in the ORAL Sync mean MTX dose was 14mg/week,21 and in the ORAL Scan doses ranged between 15 and 25mg/week.22 Recent real world evidence have shown that in daily practice MTX doses combined with TFC are close to those reported in the RCTs.24

MTX doses in combination with BARI in the published RCTs are also variable,25 mainly from 10 to 25mg/week. Mean doses are quite similar to those in TFC trials, like in the RA-Beam study (15mg/week).25

The same considerations exposed for bDMARDs are applicable for tsDMARDs. A post hoc analysis based on pooled data from 2 RCTs in Japanese patients, showed that tofacitinib efficacy may be unaffected by background MTX dose.26 At month 3, ACR20/50/70 response rates, mean DAS28-4 (ESR) CFB and HAQ-DI CFB were similar across different MTX doses.

The panel agreed that in patients who have achieved and sustained the treatment goal, the de-escalation of the bDMARDs (irrespectively of the type) should be considered. The term ‘sustained’ is still not defined precisely, but at least 6 months was delimited as a minimal time frame. However, on the other hand, this does not exclude MTX dose adjustments (along with the de-escalation of the bDMARDs) or even MTX withdrawal in some intolerant patients on IL-6 inhibitors. Moreover, in some cases, the adjustment of MTX doses could even be the first step (before the de-escalation of the bDMARDs).

In this context, the TNF inhibitor tapering after attainment of remission in early and established RA allows excellent outcomes to be maintained.27–29 The PRESERVE study, a RCT comparing the safety and efficacy of once-weekly ETN 50mg, ETN 25mg, and placebo in combination with MTX, analyzed radiological progression between groups of patients continuing full-dose ETN with patients switching to half-dose or stopping of ETN. There were no differences in the changes of the modified total Sharp score between these groups.27 Recently, in a RCT designed to evaluate the effectiveness of two tapering strategies after achieving controlled disease in patients with RA receiving combination therapy with TNF inhibitors and csDMARDs, for up to 9 months, flare rates when tapering csDMARDs or TNF inhibitors were similar. Moreover, after 1 year, anon-significant difference was found between them.30

On the other hand, in a non-inferiority RCT, RA patients on TCZ+MTX and good/moderate EULAR response were randomized to tapering MTX or continuing stable doses of MTX for 24 weeks.31 Although the study stopped early due to low recruitment, the predetermined non-inferiority criteria were still met. Therefore, tapering MTX in patients with RA receiving TCZ was non-inferior to continuing stable MTX in maintaining a good/moderate EULAR response. In another double-blind RCT in biologic-naïve RA patients with a disease activity score 28 (DAS28)>3.2 despite oral MTX, treatment with TCZ+MTX was prescribed for an initial 16 weeks period. Patients who achieved low disease activity (DAS28 ≤3.2) were randomised to continue with TCZ+MTX or switch to TCZ+placebo for an additional 12 weeks. In both treatment groups, the percentage of patients in clinical remission from 16 to 28 weeks was similar, as were the improvements in disease activity, functional disability and quality of life.32 However, as the authors comment, the short period of 12 weeks on TCZ monotherapy after randomisation in JUST-ACT does not allow for a long term evaluation of response maintenance, which may theoretically influence our results.

The SMART study was an open-label non-inferiority study in patients with an inadequate response to TNF inhibitors in which all patients on RTX 1000mg+MTX and a moderate or good EULAR response were randomized to RTX 1,000mg for 1 or 2 doses.33 Over 104 weeks, the adjusted mean difference in DAS28 area under the curve was 51.4 (95% CI −131.2 to −234), indicating non-inferiority (as it was pre-defined) between the two doses.

Dose reduction of ABA to half-dose (plus other DMARDs mainly MTX) in patients with early RA was evaluated in a sub-study of the AGREE trial.34 At 1 year, 34% (half-dose) and 31% (full-dose) of patients experienced a flare.

Regarding to the JAKs inhibitors, we need more studies to make robust recommendations.

As previously suggested in the Spanish REDOSER project, the panel considered that rheumatologists should individualize every case and consider tapering in clinical situations in which down titration will likely be successful, related primarily to early RA, depth of improvement and duration of remission.35

TNF inhibitors efficacy and safety in combination with MTX or leflunomide (LEF) was analyzed in the RABBIT biologics registry.36 EULAR response rates after 24 months ranged from 74% to 81% for combinations with MTX and 72% to 81% for LEF (P<.050). The safety profile was the expected when using these drugs. Regarding ABT, a post-hoc exploratory analysis from 3 interventional trials and 1 real-world study, showed the efficacy and safety data extracted from RA studies in which ABT combination with csDMARDs other than MTX was permitted. At 6 months and 2 years, the efficacy (DAS28 and HAQ) was similar for combinations of ABA+MTX and ABA+other csDMARDs like LEF, hydroxychloroquine, SZZ or azathioprine.37 The CERERRA Collaboration (10 European biologics registries) found that significantly more patients achieved a EULAR good response at 6 months when treated with RTX plus mean LEF doses of 20mg/day (29.1%) compared with RTX plus mean MTX doses of 14.4mg/week (21.1%). Similar results were observed at 12 months. Adverse events (AE) occurred in 10.2% and 13.2% of patients, respectively.10 There are also RCTs of IL6 inhibitors that included patients in combined therapy with different csDMARDs but no comparative data were shown.13 A small observational study did not find efficacy or safety differences between TCZ+MTX and TCZ+LEF.38

On the other hand, MTX in combination with TNF inhibitors has largely demonstrated to increase this group of biologics survival.39,40 However, connected to ABT, RTX and IL6 inhibitors, so far MTX has not clearly been associated with longer survival.41,42

Some bDMARDs are associated with immunogenicity (and impact on clinical efficacy and safety) that might be attenuated with the concomitant use of MTX.43–45 The positivity of anti-drug antibodies to TNF inhibitors occurs in about 13% of patients but varies greatly, depending on the specific TNF inhibitors, with the highest rates observed with IFX and ADA, and the lowest with ETN.43–45 Several studies have confirmed that in patients treated with IFX, ADA, CZP or GOL, the combination with MTX decreases the rate of anti-drug antibodies.45,46 Data related to ABT, RTX and IL-6 inhibitors suggest that these drugs are clearly less immunogenic.45,47 However, it should be taken into account that immunogenicity of individual agents has been analyzed using different study designs, treatment duration, RA characteristics, as well as a great immunoassay heterogeneity. Therefore, data interpretation is challenging and should be carefully considered.48

Finally, regarding the use of parenteral MTX, although more data is still needed, observational studies have shown that its efficacy and safety when combined with bDMARDs are similar to those with oral MTX.2,49,50

Up to 86% of patients from TFC’ RCTs on combined therapy use MTX,51 although there are also some patients taking other DMARDs like LFN, antimalarials, SZZ, sodium aurothiomalate or D-penicillamine.51 However, comparative analyses are not available. BARI RCTs have reported the same data. In terms of survival, a pooled analysis of TFC studies found that up to week 72, the discontinuation rate when receiving combination therapy with a csDMARD (86.2% MTX) was 50.7% vs 45.2% of patients receiving TFC monotherapy.52

Nevertheless, so far TFC and BARI are not immunogenic drugs, and more studies are necessary to assess the role of parenteral MTX in patients with JAK inhibitors.

Pooled data from RCTs have depicted that MTX and bDMARD combination therapy is not significantly associated with an increased risk of serious AE, serious infections or death when compared with bDMARD monotherapy.53 However, an increase risk of gastrointestinal AE(including hepatic AE) has been reported with the combined therapy.7 Observational studies including biologic registries have also found no increased risk in other relevant AE like cancer.54

As a result of all data exposed above, the panel considered that risk management when combining MTX with b- or tsDMARDs should be the same as for their individual components.55