This publication forms part of the NEXUS Project. This is led by 2 national coordinators (rheumatologist experts) and comprises 8 work groups, each with a regional coordinator and 2 or 3 reviewers (depending on the group), for a total of 22 reviewers. Every year different subjects of interest in the field of RA are analysed. In the 2017–2018 issue this was the use of corticosteroids and combined therapy with synthetic DMARD in RA. In this publication we describe the SLR referring to the question on combined therapy in RA. The Spanish Society of Rheumatology guarantees that the methodology used is appropriate, but does not endorse the conclusions because the Spanish Society of Rheumatology has official policies in this regard.

Initially, one of the national coordinators put forward the following questions which were responded to through an SLR:”In early RA patients, is combined therapy with synthetic DMARD better than sequential therapy with synthetic DMARD? In established RA patients who are refractory to standard first line therapy (synthetic DMARD), is the combination of MTX+LEF or triple synthetic DMARD therapy effective and safe?” The SLR protocol was defined with these questions.

The 2 clinical questions were transformed into the PICO with which the inclusion and exclusion criteria were defined. For the first questions we selected studies which included patients with RA (international criteria or clinical judgement), early RA (≤2 years onset) adults (≥18 years), DMARD naive; being treated with combined therapy (double or triple) with synthetic DMARD with or without corticosteroids or other adjuvant drugs. Comparative studies had to have synthetic DMARD in sequential therapy (monotherapies or DMARD therapy with add-on drugs).

For the second question we selected studies which included patients with RA (international criteria or clinical judgement), adults (≥18 years), established RA (> 2 years onset), refractory to standard first line treatment (synthetic DMARD); being treated with combined MTX and LEF therapy or triple therapy with synthetic DMARD, with or without corticosteroids or other adjuvant drugs.

In both questions articles were sought whose outcomes analysed efficacy and safety variables regularly used in the study of RA. Finally, only those studies with the following designs were included: met analysis, systematic reviews and randomised clinical trials (RCT). Studies on animals and basic science were excluded.

Aided by an expert documentalist search strategies were created for the different databases. For this they used the MeSH terms and terms in free text. Only articles on humans, in English or Spanish were included in the search.

For this review the following bibliographic data bases were screened: Medline, Embase and Cochrane Library (all from their initiation up until July 2017). Due to the volume of bibliographic references recovered, we decided not to review the grey literature of the main national and international rheumatology conferences. A manual search was subsequently performed secondary to the bibliography of the articles finally included. The supplementary material shows the search strategy used, together with the number of references collected.

All the references resulting from the searches were inserted into the EndNote programme for easier management.

Following this, 2 reviewers created the first selection of articles resulting from the search strategy by reading the title and abstract, complying with the inclusion and exclusion criteria, each independently. Whenever a discrepancy arose, a third reviewer was taken on board to make a decision. After this, 11 reviewers made a second article selection through independent detailed reading and applying the same inclusion and exclusion criteria. To do this, the number of references collected was equally distributed among the 11 reviewers. Whenever a discrepancy arose, the other reviewer of the previous phase resolved the problem. In Fig. 1 we show the flow diagram of the selection process of the articles, and in the supplementary material, the characteristics of the studies included and excluded.

Fig. 1.

Flow diagram of studies.

(0.14MB).

The 11 reviewers and one of the reviewers from the first selection stage, collected the study data included using specifically pre-designed templates). The Jadad12 scale was used to assess the methodological quality of the studies included. Again, where discrepancies arose the other reviewer from the previous stage resolved the problem.

Tables of evidence and outcomes were created, where the main characteristics and outcomes of the included studies were described. Some of these were expressed as numbers and percentages (%), mean and standard deviation, mean and interquartile range (p25–p75), others as odds ratios, relative risk or hazard ratios and their 95% confidence intervals (CI). The possibility of performing meta-analysis was only assessed where there was homogeneity.

During a 2-day nominal group meeting which all NEXUS Project members attended, the outcomes of the SLR were presented and discussed. A series of recommendations were agreed to. Each of the recommendations, with guidance from the methodologist, was assigned a level of evidence and a level of recommendation, in keeping with the recommendations for evidence-based medicine from the Centre for Evidence-based Medicine in Oxford.13

The BeSt study was a study designed to analyse, the effect of different treatment strategies in early RA. Patients were assigned to one of the 4 groups and if there was no response a therapeutic decision was quickly taken.14–26 Patients therefore changed therapy (within their group) and even passed from one treatment branch to another. These groups were as follows: group 1 sequential monotherapy, group 2 combined sequential therapy (staged, i.e. monotherapy initiated and if response was insufficient another drug was added on), group 3 combined therapy with MTX+SSZ+prednisone (high doses with fast dose reduction) and group 4 combined therapy MTX+infliximab (IFX). Data of up to 10 years follow-up was available, where the RA activity was evaluated, in addition to function, structure damage, quality of life and safety.

In the BeSt study, after one year,17 the groups treated with MTX+SSZ+prednisone and MTX+IFX, demonstrated better control of the activity, function, radiographic damage progression than the other groups although they also presented with more adverse events (AE), with no differences being observed in bone mineral density. Progressively, in years 2–5,16,19,20,26 these differences between the groups practically disappeared and specifically after 5 years,20 48% of the patients were in clinical remission (DAS28<1.6) and 14% in drug-free remission, regardless of the initial treatment group. After 5 years it was published that radiographic damage was lower in those patients who had started treatment in one of the combination groups.20 After 10 years a subanalysis of ACPA-negative patients was performed reporting that the early use of MTX+SSZ+prednisone and MTX+IFX was more effective compared with MTX as monotherapy.

Three good quality RCT27–29 were found (one is really data added onto the other 2 studies). They include almost 1000 patients with RA, mostly established RA (mean duration from 5 to 18 years) and refractory to standard synthetic DMARD, especially to MTX (Table 2). MTX was prescribed at a dose of 10–20 milligrams (mg)/week and LEF between 10 and 20mg/day. MTX in monotherapy was compared with MTX+etanercept (ETN), MTX+hydroxychloroquine (HCQ) and rituximab (RTX). All the patients included could take prednisone (up to 10mg/d). These RCTs analysed the efficacy (activity, function, quality of life) and safety of this combination up to 24 weeks.

The combination of MTX+LEF was statistically superior to MTX in monotherapy in ACR 20, 50 and 70, HAQ and SF-36 after 24 weeks of treatment in one of the RCT.28 However, another 16-week study found that, although all of the combinations analysed improved the activity and function of the patients, the combination of MTX+ETN was higher than MTX+LEF in many of the variables which evaluated the activity of RA (ACR 20, 50, 70, DAS28, CDAI) and the function. Furthermore, in this study it was not possible to show the superiority of MTX+LEF compared with MTX+HCQ or MTX+SSZ in these patients.27 In the third study included, the combination of MTX+LEF was similar to MTX+RTX (at intravenous doses of 500mg in 2 doses) to improve the activity (evaluated among others with the DAS28 and the EULAR response), in changes in the acute phase reactants and depending on the patients at 24 weeks.

Regarding safety, the expected AE were reported with the use of these DMARD, such as nausea, diarrhoea or elevated transaminases.27–29

With regards to efficacy and safety of the triple therapy in established and refractory RA, the SLR included 3 good quality RCT,30–33 which analysed the triple therapy with synthetic DMARD in patients with RA, most of which were established (Table 3). The duration of the RCT was from 1 to 2 years, and included over 400 patients with RA of 6–10 years onset, active (DAS28 mean of 6), refractory to synthetic DMARD. In all cases the triple therapy consisted of MTX at a dose of 20mg/week, SSZ 1–2g/day and HCQ 400mg/day. The comparators in these RCT were MTX as monotherapy, MTX+HCQ and ETN+MTX. All patients included could take stable corticosteroid doses (≤10mg/d) and triggers evaluated were the RA activity (clinical and analytical), overall patient assessment (OPA), structural damage and safety.

In the first RCT,32 published in 1996, triple therapy was significantly superior to MTX as monotherapy for improving the number of swollen joints, the OPA score and the physician global assessment (PGA). Equally, the combination of SSZ+HCQ improved the number of swollen, painful joints and the PGA, from medium to long term (2 years). Notwithstanding there were no differences in the ESR and duration of morning stiffness. Neither were there any differences in terms of safety.

The RACAT study was a RCT of non inferiority, in which the triple therapy(MTX+SSZ+HCQ) was compared with the combination of MTX+ETN. After 24 weeks of treatment, MTX+ETN was statistically superior to the triple therapies in the percentage of patients who achieved low activity DAS28 (24.8% vs 34.8% P=.050), remission-DAS28 (12.7% vs 21.7% P=.030) and ACR70 (5% vs 16% P=.001), with no differences in the other variables, including the reduction mean of the DAS28 which was the mean of the main trigger. However, after 48 weeks (where the patients could be assigned to the other branch if response was insufficient), there were no statistically significant differences between groups relating to RA activity (DAS28, CDAI, ACR response 20, 50, 70), the HAQ and radiographic progression (Table 3). In open extension at 72 weeks,30 adherence to treatment at one year was higher in the ETN+MTX group than in the triple therapy group, 78% vs 63%, and changes of regimen were higher from triple therapy to ETN+MTX than the inverse (p=.005). The DAS28 continued to improve with no statistically significant differences between the groups.

Regarding safety, the expected AE were reported for the use of these DMARDs, including infections and gastrointestinal disorders.30–32