A prediction rule for lack of achievement of inactive disease with methotrexate as the sole disease-modifying antirheumatic therapy in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a chronic and heterogeneous disease characterized by prolonged synovial inflammation that may cause irreversible alterations of articular structures [1]. Joint changes can lead to serious impairment of physical function and have a major impact on the quality of life of children and their families [2‐4]. It is now well established that minimizing disease activity over time reduces progression of joint damage and improves functional outcome in patients with chronic arthritis [5‐7]. These observations, together with the recent therapeutic progress, have moved the therapeutic aims increasingly towards the attainment of an inactive disease status [8‐10].

Methotrexate (MTX) is the cornerstone synthetic disease-modifying antirheumatic drug (DMARD) for the treatment of JIA [11‐13]. It is an inexpensive and safe medication, and has been shown to be beneficial in 60–70% of patients both in randomized controlled trials and observational studies [14‐17]. However, most analyses have evaluated the effectiveness of MTX in terms of percentage of improvement in clinical and laboratory indices of disease activity, whereas its capacity to induce complete disease quiescence has been seldom investigated [18‐20]. Considering that current clinical practice mandates good overall disease control, to gain further insight into the therapeutic efficacy of MTX there is a need to obtain more information about its disease-remitting potential.

Because it is still impossible to predict the disease course in the individual patient and, hence, the treatment requirements at the onset of the disease [13, 21], a step-up approach is generally pursued of starting MTX and adding a biologic DMARD if the patient does not respond sufficiently well to MTX. However, given the abovementioned goal to start effective treatment immediately in order to prevent joint damage and the notion that MTX is not efficacious in a sizeable proportion of patients, it is essential to distinguish beforehand the patients who are likely to respond well to MTX from those who are not. The latter group may deserve prescription of a biologic DMARD from the outset. Over the years, several studies have sought for predictors of MTX efficacy. However, most of them have focused on the American College of Rheumatology (ACR) pediatric level of response (which emphasize percentage change), whereas the achievement of the state of inactive disease (ID) has rarely been used as endpoint [13, 22, 23].

Against this background, the primary aim of the present study was two-fold. First, we investigated the frequency of achievement of ID in children with JIA treated with MTX as the sole DMARD. Second, we aimed to develop a prediction model that could help to identify at treatment baseline the patients with a lesser likelihood to reach ID with MTX.

In the present study, we investigated the frequency of attainment of ID in 375 children with JIA seen between 2000 and 2013 who received MTX as the sole DMARD, with or without concomitant administration of NSAIDs or systemic or intra-articular corticosteroids. Of the two routes of corticosteroid administration, the intra-articular one likely played a greater synergistic role with MTX as 44.1% of patients were given corticosteroids intra-articularly and only 8.8% systemically during MTX administration. Patient follow-up was censored at the time of the occurrence of the first episode of ID, at last follow-up visit with persistently active disease, or when the caring physician deemed necessary the start of a biologic DMARD because of persistently active disease despite MTX therapy. Thus, the results of our study provide insights on the potential to achieve complete disease quiescence with conventional (i.e. non-biologic) treatment. As such, they offer a measure against which outcomes from other cohorts may be judged and a benchmarking for outcome comparisons with recent cohorts treated with more aggressive approaches, based on earlier introduction of biologic DMARDs or with the treat-to-target strategy [9, 28, 29].

We found that 61% of patients achieved ID after a median of 1.7 years from the start of MTX therapy. The relative frequency of favorable outcome was higher among patients with oligoarthritis than in those with ERA or systemic arthritis; an equal proportion of patients with polyarthritis reached or did not reach ID. Note that in the study period it was our policy to inject with corticosteroids all active joints at presentations in each patient with oligoarthritis. MTX was started at the time of intra-articular therapy in most of these patients, except those with knee monoarthritis who received their first injection [30]. The results of our study are not easily comparable with those reported in other series of JIA patients treated with MTX because of differences in proportion of disease categories, length of follow-up, treatment regimens, concomitant therapies and outcome endpoints. In a recent German national multicenter study, a similar proportion (68%) of biologic-naïve patients who were started with MTX experienced at least one episode of ID [23].

In univariate analysis, patients of male gender and with older age at disease onset, ERA or systemic arthritis, absence of ANA, and higher ESR and CRP, and patients treated with parenteral MTX and given systemic corticosteroids before and during MTX administration were less likely to attain ID. The lesser responsiveness to MTX of patients with systemic arthritis is in keeping with the well-established notion that this JIA category is scarcely susceptible to this drug, particularly in the presence of active systemic manifestations [31]. MTX is also known to be distinctively less effective in ERA, for which current therapeutic recommendations advice the use of sulfasalazine as primary synthetic DMARD [26]. The predictive role of male gender and older onset age is likely related to that of systemic arthritis and ERA, in which these features are more prevalent than in the other forms of JIA. The relationship between absence of ANA and poorer efficacy of MTX agrees with the previous demonstrations of ANA-positivity being a marker of better response to MTX [13, 32‐35]. Elevated acute phase reactants were found by Bulatovìc et al. [35] to be associated with lack of achievement of ID with MTX therapy. The association of parenteral MTX with worse outcome may reflect our policy to switch from the oral to the parenteral route or to start MTX parenterally in the most severe or refractory patients. Likewise, patients treated with systemic corticosteroids were those with systemic arthritis or more severe polyarthritis, who have an underlying high risk of poorer therapeutic response.

The variables that remained independently associated with lack of attainment of ID in the best-fitted model of logistic regression procedures were systemic arthritis, ERA, polyarthritis and elevated CRP. Based on the results of multivariable analysis, we devised a prediction score for lack of achievement of ID with MTX as the sole DMARD, which ranged from 0 to 3. The score cutoff that discriminated best between patients who achieved or did not achieve ID was > 0.5, which means that patients with a score ≥ 1 are less likely to attain ID with MTX as the sole DMARD. Thus, a diagnosis of systemic arthritis or ERA, both of which had a score greater than 0.5, was sufficient alone to predict a lower likelihood to reach ID. Polyarthritis and increased CRP, whose score was 0.5, assumed a predictive value only when present in association.

A number of caveats should be considered in interpreting our findings. The study design was retrospective, which implies the risk of missing or possibly erroneous data. Our results reflect a single-center experience, which means that they may not be generalized to series followed in other settings. Because our analysis was nonrandomized and observational, we cannot exclude that patients who achieved ID had a less aggressive disease than those who did not. In this respect, the overrepresentation of the oligoarticular phenotype, which is regarded as the most benign JIA subset, might partly explain the favorable outcome figures. The median time interval of 1.7 years between MTX start and achievement of ID would nowadays be regarded as too long. Contemporary treatment strategies mandate an earlier achievement of complete disease control [9, 10]. We recognize that the AUC of the predictive model as well as the sensitivity and specificity of the score cutoff were only fair. Thus, the prediction model needs to be tested in a validation cohort prospectively. The use of logistic regression cannot account for the different length of follow-up time for each patient. A time-to-event hazard model would have been more appropriate to address this issue. Achievement of ID was only assessed at a single point in time and not in terms of time spent in ID. Several studies have shown a high risk of disease flare after MTX discontinuation for clinical remission in children with JIA [20, 23, 36]. We should finally recognize that in a number of patients the state of ID could not be established formally according Wallace criteria, owing to the lack of the physician global assessment, but was inferred through the review of clinical charts.

In conclusion, we found that a conventional treatment regimen based on the use of MTX as the sole DMARD led to the achievement of ID in a sizeable proportion of children with JIA. Patients with systemic arthritis, ERA and polyarthritis with increased CRP were less likely to achieve ID. These findings help to outline the characteristics of JIA patients who may deserve the prescription of a synthetic DMARD other than MTX or the introduction of a biologic DMARD from the disease outset.