Matrix to predict rapid radiographic progression of early rheumatoid arthritis patients from the community treated with methotrexate or leflunomide: results from the ESPOIR cohort

The care of rheumatoid arthritis (RA) has profoundly evolved during the last decade because of new drug therapies and the early treatment paradigm. RA requires rapid referral to a rheumatologist [1‐3] and early initiation of disease modifying anti-rheumatic drugs (DMARDs) to prevent long-term disease consequences, such as diabetes or hypertension [4, 5]. At the same time, regular adaptation of DMARDs depending on disease activity - that is, RA tight control - has become an additional standard in RA management to achieve at least low disease activity and, if possible, disease remission [3, 6‐12]. Implementation of these recommendations in practice has led to better clinical outcomes [6, 8, 13].

The choice of the first DMARD has been the topic of many trials and guidelines. Methotrexate (MTX) has been recommended as the anchor drug because it allows for step-up strategies, that is, the addition of other synthetic or biological DMARDs if adequate response is not achieved with MTX monotherapy [3, 9, 14]. Leflunomide is the alternate choice because both drugs seem to have equivalent symptomatic and structural efficacy [15]. A number of trials have assessed the potential benefit of biologic DMARDs as first-line treatment for early RA [16‐18]. These intensive options have been considered more efficacious than MTX in trials with a static therapeutic strategy during the first year [18]. However, in trials adopting dynamic step-up strategies, the overall benefit of biologics as a first-line agent remained questionable [6, 11, 12, 19‐21]. In addition, several economic evaluations reported that incremental cost-effectiveness ratios of biologics as first-line treatment for early RA are usually high and largely overtake the generally accepted thresholds [22, 23]. These conclusions reinforced the position of MTX (or leflunomide) as the optimal first-line agent for early RA.

Despite current recommendations, for some patients, MTX may be suboptimal as first-line therapy. Several trials have shown substantial structural progression even with MTX started rapidly after disease onset. This situation has led to the development of the concept of rapid radiographic progression (RRP), defined as structural damage progression of at least five points of the van der Heijde-modified Sharp score (vSHS); the cut-off of five points corresponds to the destruction of one small joint and to the usually reported smallest detectable difference (SDD) [24‐26]. The rationale for this threshold has been confirmed in two different studies. In the BeSt trial, patients with RRP during the first year of follow-up showed increased functional limitations and structural damage progression over eight years of follow-up, despite a tight control-based therapeutic strategy [27]. These results are consistent with another study of the ESPOIR cohort in which patients with RRP during the first year in the cohort, with a definition slightly different from the previous one, showed increased structural damage progression during the second and third years in the cohort [28].

The poor prognostic value associated with RRP is important and may be addressed by the development of prediction matrices to quantify the risk of RRP at one year in terms of baseline data. Such matrices are a tool than can identify patients with early RA who will show inadequate response to MTX or its equivalent [24, 29‐31]. These matrices have been developed in randomized clinical trials of patients with aggressive disease, who are not generally representative of patients with early RA. Therefore, the use of these matrices is limited in clinical practice, as was recently shown in the BRASS cohort [32].

Thus, we conducted a study of data for the ESPOIR cohort, which enrolled patients with early arthritis from the community (with or without unfavorable prognostic factors). We aimed to develop a prediction algorithm and matrix to identify patients with early RA at risk of RRP despite early synthetic DMARD initiation.

The present study allowed for the construction of a matrix to predict the risk of RRP for patients with early RA despite MTX or leflunomide therapy. Since RA is considered a medical emergency [39] requiring rapid referral to a rheumatologist [1‐3] and early initiation of DMARDs to prevent disease progression, the ESPOIR matrix might help rheumatologists in daily practice identify patients at high risk of SD failure, and thus make better-informed and evidence-based therapeutic decisions. The community-based nature of the study is one of the major strengths of this work, which makes patient typology more representative of daily clinical practice than that of randomized clinical trials. The ESPOIR cohort included patients with early arthritis and possible, probable or definite diagnosis of RA. However, no specific disease activity level or prognostic markers of severity were required for inclusion [33].

For several reasons, we focused on patients who had started receiving MTX or leflunomide during the observation period. First, therapeutic decisions were not protocol-based in the ESPOIR cohort, and patients received treatment according to standard care by their rheumatologist. Patients with the most active or structurally aggressive disease were more likely to receive the most effective drugs such as MTX or TNF blockers, which highlights a channeling bias [4, 40]. Four gross therapeutic strategies can be distinguished: no DMARD during the first year in the cohort, DMARDs without demonstrated structural efficacy such as hydroxychloroquine, DMARDs with demonstrated structural benefit such as MTX or leflunomide, or biologics such as TNF blockers. Without any adjustment, the progression in vSHS was substantially higher in the latter two groups, which shows that patients receiving the most efficacious drugs were identified by their rheumatologists as being likely to have active and erosive RA [4]. The use of propensity scores could in theory adjust on these confounding factors. Although different models were tested, we did not achieve a satisfactory adjustment, able to make the different treatment groups comparable at baseline. Thus, the analysis was stratified and only focused on the more clinically relevant and adequately sample-sized group, that is, the group of patients treated with either MTX or leflunomide, the two most widely used therapies in early RA. Although several synthetic DMARDs have shown their ability to prevent structural damage progression, only two seem to have similar efficacy (that is, MTX and leflunomide) in a recent systematic literature review conducted under the auspices of EULAR [15]. Therefore, sulfasalazine, gold salts or other synthetic DMARDs were excluded in the patient selection process. This choice also appeared more clinically relevant because this therapeutic option is considered optimal for most patients [17]. Our data indicate that other options, for example, biologics, could be better for the patients with high RRP risk (red boxes in Figure 1). In an explanatory analysis, the patients treated with TNF-blockers as first line agent (n = 37, with complete data available for only 27) were plotted in the matrix; their observed RRP risk was lower than the expected RRP risk.

Several prediction matrices have been recently proposed. Three were derived from results of randomized controlled clinical trials assessing the efficacy of TNF-blocking agents [20, 24, 29‐31, 41], so patients with early RA with substantial disease activity and/or severity were included as candidates for biologics. Moreover, in these trials, therapeutic adaptation was protocol-based - fixed strategy over one year or tight control according to a predefined scheme - which, in both cases, is not quite consistent with usual care in which treatment adaptations are often looser, thus enabling suboptimal disease control [42, 43]. Only one algorithm was developed from data from an early RA cohort, SONORA, in Canada and the United States but has not been published [44]. The predictors identified to build the different matrices were partly overlapping. In the ASPIRE matrix [24], the three constitutive variables comprising the matrix were RF status, SJC and erythrocyte sedimentation rate (ESR); baseline joint damage was not included, although it is a strong predictor of further structural damage in RA [45]. In the BeSt study [30], RF or ACPA status, number of erosions at baseline and CRP level but not SJC, another marker of disease severity, were used in the risk matrix [45]. In the SWEFOT trial [20, 29, 31, 41], the proposed matrix included smoking status, CRP level and erosions at baseline; ACPA status was not significantly associated with RRP, which is not consistent with the literature [45]. This finding may be explained in part by the confounding of the strong association of smoking status and ACPA status [46‐48]. The ESPOIR matrix may appear more comprehensive than the other matrices because it included all the known RA prognostic markers. Of interest, in the observational cohort SONORA, the proposed matrix included most of the same parameters: baseline DAS28(ESR)-4v, vSHS and ACPA status [44].

Our study has some limitations. The first pertains to MTX dosage, because several doses have been proposed in the literature. Our patients received 17.5 mg/week, on average, which may be considered slightly lower than that used in other settings [49]. Another concern relates to low-dose prednisone therapy, which has been efficacious in preventing structural damage progression [50‐52]. In the ESPOIR cohort, 42% of the patients received steroids during the first year of follow-up, with a mean dose of 5.5 ± 3.7 mg/d (median 5 mg/d). This daily dose was quite low, and our analyses did not reveal any association between prednisone intake and RRP.

The quality of care could not be assessed in the ESPOIR cohort, especially in terms of optimal or suboptimal timing of RA diagnosis or MTX introduction, two key elements of future disease control [3, 4, 13, 53]. Moreover, the implementation and respect of tight control was not identifiable in the cohort and may have had an impact on structural progression [42]. However, this situation may suggest that our results are representative of clinical practice, as stated above. Another important limitation is the lack of validation of our matrix in a different population, which is a limitation in all RA matrices. Attempts have been made to cross-validate the ASPIRE, BeSt and SWEFOT matrices in the SWEFOT trial population [41] and in the BRASS cohort, an established RA cohort [32]. In both cases, the performance of the different matrices in different populations was disappointing. Whether the more comprehensive ESPOIR matrix may be optimal in different populations remains to be demonstrated, as well as the performance of the other matrices in the ESPOIR population (work in progress). Finally, all matrices have limitations inherent in their development that relate to multivariate analyses performed in limited samples of patients. The RRP risk was thus a predicted risk as opposed to an observed risk. Some of the matrix boxes were rather poorly populated and may explain the only fair performance of matrices in populations different from those in which they have been developed.

The ESPOIR matrix is a novel tool developed in a real life setting to help rheumatologists in usual daily practice to identify patients with early RA at high risk of RRP despite MTX or leflunomide therapy. The performance of this tool needs to be validated in other patient populations. Then, it will become a quite relevant instrument to guide rheumatologists in their therapeutic decision making, especially to detect patients for whom MTX may not be optimal therapy.