Studies such as this provide evidence of effective “building blocks”, which can be used to achieve tight control of rheumatoid arthritis. Although a fixed combination of DMARDs within a rigid protocol will inevitably have limitations, this true‐to‐life study nevertheless yields useful results. Thus, 28% of the patients with rheumatoid arthritis (most of whom had early inflammatory arthritis) showed “too good” a response to SASP alone to warrant consideration for combination therapy. A further 19% were withdrawn because of reversible side effects in the first 6 months, and were ineligible for combination therapy.
In those with an inadequate response, 165 agreed to enter phase II—after 12 months, the combination of SASP and MTX was superior to monotherapy with either drug, and no additional toxicity was observed. The MTX alone arm was at a slight disadvantage because of the lag phase before the drug became effective.
As DMARD therapy in rheumatoid arthritis needs to be sustained, if benefit is to be shown, tolerability is of importance. The “intention‐to‐treat” approach showed that no harm had resulted from combination therapy. Although 25% of the patients in SASP, 30% in MTX and 30% in combination groups did not complete 18 months of therapy, efficacy was greater with combination compared with SASP or MTX alone.
An in vitro study from Jansen et al34
concluded that the potent SASP inhibition of reduced folate carrier may lead to lack of additivity when SASP and MTX are used together, suggesting that the in vitro effect is not relevant to use in vivo.
Unlike studies undertaken for regulatory approval or those including anti‐TNFα treatments, this study had a “true‐to‐life” recruitment protocol with very few exclusion criteria, making these results applicable to routine clinical practice. Most patients had early disease (70% <1 year, 22% 1–5 years) and 8% had a disease duration of 6–10 years; minimisation ensured distribution of disease duration between the three groups.
This inexpensive intervention of a “step‐up” combination of SASP and MTX therapy proved effective and affordable in an unselected population of patients with rheumatoid arthritis. Although the extent of benefit observed was relatively modest, a small beneficial shift across large numbers of patients is relevant to the rheumatoid arthritis population in general, and other drugs—eg, hydroxychloroquine—could then be added in some patients. This strategy costs only 2% of that using anti‐TNF therapy, and is not associated with increased toxicity. These findings should have a direct benefit to patients with rheumatoid arthritis and allow clear protocols to emerge. Further studies to determine which patients would benefit from a third additional treatment, and to what extent this would prevent radiological progression of disease are still required. This information is needed to work towards tight control strategies in all patients with rheumatoid arthritis.
This study was not powered to show slowing of radiological progression, and predictably this was not observed. In part, the very small number of erosions over a relatively short period (18 months) limits the usefulness of radiological assessment, and other studies have not attempted x ray scoring in this setting. Similarly, function as determined by the health assessment questionnaire is a multifactorial measure, of which synovitis is one component.
The “step‐up” approach was used rather than “sustained continuous” or “step‐down” regimens, because this approach is often adopted in clinical practice. In a double‐blind controlled randomised study, O'Dell et al
compared parallel sustained treatment with MTX, SASP and HCQ against MTX alone, and SASP and HCQ in patients with established rheumatoid arthritis.10,11
Low‐dose oral prednisolone was permitted in their studies. Although the patients had more severe disease than in the Management of Atrial Fibrillation (AF) Suppression in the MASCOT study, the results are comparable, as both showed improvement in measures of clinical synovitis, but no difference in ESR as a single measure. O'Dell et al
did not report on radiological outcome.
Other studies reporting the benefit of sustained initial combination therapy with either MTX and SASP, or MTX, SASP and HCQ have been open or single‐blind studies, and not all were randomised. Most have shown that the three drugs combined is better than a combination of two drugs or single agents. Only one study has reported that radiological outcome is better in those receiving a combination of MTX, SASP and HCQ.9
One open step‐up study of this combination showed benefit,4
but two double‐blind placebo‐controlled studies have shown that the combination of MTX and SASP from the outset showed only a trend to superiority over monotherapy with either agent.5,6
The differences between our results and these studies may simply be that a step‐up approach selects a subgroup of patients more likely to derive benefit.
The use of targeted biological treatments is an alternative to combinations of small‐molecule conventional DMARDs. When used with MTX, all the licensed anti‐TNFα treatments in early disease show benefit over MTX, but at a greater financial cost, and with, to date, unknown long‐term toxicity.22,23,24,25
A direct comparison of anti‐TNFα treatment with standard approaches in the BeSt study (single‐blind design18
) confirmed that a step‐up approach was superior to sustained monotherapy, with no difference in the number of patients who achieved a sustained fall in DAS score
2.4 over 52 weeks in the step‐up or step‐down approach (as in the COBRA study) or with an anti‐TNFα treatment in combination with MTX. This study did, however, report earlier benefit with high‐dose steroid or infliximab, and radiological advantage at 1 year.
We followed a robust study design, but there are limitations which merit emphasis. A larger than expected number of patients eligible for phase II preferred not to enter the double‐blind phase (24%). This was also true in a previous study from this centre.32
The longer‐term outcome of this group compared with those who were randomised is being recorded. DAS tended to improve between 6 and 18 months, but did not reach significance. The effect of patient attitude on future designs of combination DMARDs and the economic evaluation of biological agents in early treatment of rheumatoid arthritis needs to be noted.
The results in terms of ACR and EULAR response are intermediate between those noted by Dougados, who added SASP to leflunomide,7
and those achieved in the TICORA8
and anti‐TNF studies. The ACR and EULAR responses have been shown to have comparable validity.35
The flexible treatment strategy used in TICORA was tailored to the needs of the individual patient, and all were seen monthly by the same rheumatologist. Although this strategy was effective, staff required for this approach are not always available because there are too few skilled healthcare workers in many areas. The addition of an anti‐TNF drug is expensive, in some instances prohibitively so. There are also uncertainties about toxicity in a true‐to‐life setting and in the long term. It is anticipated that this information will emerge from ongoing prospective data registries in several countries.
For health resource planning, this study provides precise information about how often unselected patients show sufficient response to their initial DMARD (SASP), and hence do not require additional therapy, and about the proportion who refuse a combination even when disease activity suggests that this would be valuable.
This combination study shows that step‐up treatment for patients with an inadequate response to SASP is of significant clinical benefit, carries no additional toxicity and is achievable at minimal extra cost, an important consideration in the responsible use of healthcare resources.