Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease characterized by chronic arthritis with no further cause [1]. JIA is a diagnosis of exclusion and embraces a rather heterogeneous patient cohort [2]. Nevertheless, the most pronounced clinical and laboratory manifestations in these patients allow them to be combined into several JIA categories with respect to the International league of Associations for Rheumatology (ILAR) criteria [3]. For several JIA categories, own recommendations for patient management and treatment regimen exist [4]. Patients with polyarticular JIA who have no systemic manifestations can be treated with either non-steroidal anti-inflammatory drugs (NSAIDs) or intra-articular injections of glucocorticoids (GCs) as the first-line therapy depending on the presence of poor prognosis features. The efficacy of methotrexate (MTX) in polyarticular JIA has been demonstrated, and thus, it is recommended as the first disease modifying anti-rheumatic drug (DMARD) [4, 5]. However, not all patients respond sufficiently to MTX, and some are intolerant of its side effects [6, 7]. According to international guidelines and recommendations, JIA patients refractory to MTX treatment are eligible for treatment with biologics [4]. In most cases, biologics are prescribed after a patient has already been unsuccessfully treated with other drugs for several months. Approval of biologics such as Adalimumab, Etanercept, Golimumab and Tocilizumab is restricted to polyarticular patients who failed pretreatment with MTX. The current treatment strategies and the sequence of medication switching allow a considerable percentage of patients to achieve long-term remission [8]. However, most questions related to the optimal treatment regimen still need to be solved. Some of these questions have been outlined in the project plan for new ACR guidelines [9] that will be issued in 2021. In particular, the question regarding anti-tumour-necrosis –factor (anti-TNF) drugs (the first-line biologics for treating arthritis without systemic manifestations) consists of choosing between biologic monotherapy and biologic+non-biologic DMARD combination therapy if a biologic needs to be added to the treatment regimen. Identifying patient categories for the optimal treatment choice is also a high-priority task. Furthermore, according to the current clinical guidelines, anti-TNF agents can be prescribed only after the disease activity remains medium or high regardless of MTX treatment for 3–6 months [4]. Such a delay prolongs the time with active arthritis, reduces the current quality of life of patients and their parents and increases the risk of developing irreversible osteoarticular changes. Therefore, a very important issue is related to changing the timing of medication switching or identifying certain subgroups/cohorts of patients for whom early treatment with biologics or combination therapy will be the most effective option. Etanercept (ETA) remains one of the most frequently used anti-TNF drugs for JIA patients [10, 11]. The development and spread of biosimilars also contribute to their wider application [12, 13]. Choosing the optimal regimen of ETA therapy is very relevant for both issues mentioned above. Even for methotrexate, which is the basic therapy option, the relationship between the duration of the disease and the effectiveness of treatment has been demonstrated to be well known [14]. One of the key questions is whether the strategy of waiting for 3–6 months to determine whether MTX monotherapy is ineffective before prescribing ETA is beneficial compared to the simultaneous prescription of a combination treatment at baseline in terms of the time to achieve remission and the long-term outcome. Wallace et al. [15] attempted to demonstrate that early aggressive therapy contributes to the earlier onset of clinically inactive disease. However, in this study, the control group received MTX monotherapy, while the main group received combination MTX + ETA+GCs therapy. That combination made it impossible to assess the efficacy of the biologic itself. Therefore, we planned and conducted a double-blind, placebo-controlled study to evaluate the effectiveness of two different treatment regimens: ETA+MTX combination therapy vs the standard MTX monotherapy with ETA added subsequently (not earlier than after 12 weeks of MTX monotherapy) in JIA patients without systemic manifestations of disease.

Our study revealed that initial therapy with ETA+MTX was already very effective after weeks 4 to 12 of treatment, with nearly all patients responding according to the pedACR30 criteria, and the response rate was significantly higher than in the placebo+MTX group. Although ETA has been studied in polyarticular JIA for 20 years, this is the first head-to-head placebo-controlled trial with ETA in these patients. A different design was used in the present study than in the TREAT study, in which patients received ETA+MTX + high-dose steroids or MTX plus two placebos for steroids and ETA [15].

The primary objective of our study was to investigate whether ЕТА + МТХ combination therapy is superior than the treatment regimen recommended by current clinical guidelines (MTX only with the subsequent addition of ETA if necessary). We have demonstrated that both treatment regimens are equally effective for achieving remission at week 48. Approximately 50% of patients reached an inactive disease state after 48 weeks of treatment. However, the effectiveness of these treatment regimens differed in terms of the time required to reach an inactive disease state. It took a median of 24 (IQR 14–32) weeks to reach an inactive disease state for patients treated with the ETA+MTX combination. Patients who had been initially treated with placebo+MTX and then switched to combination therapy (at any time) reached an inactive disease state after a median of 32 (IQR 24–40) weeks. The time to reach an inactive disease state significantly affects quality of life of patients and their parents.

The clinical response to methotrexate is known to have a delayed onset. It is thought that the polyglutamated form of methotrexate is responsible for its DMARD activity. There is usually a time lag in the efficacy of low-dose methotrexate in clinical practice, as accumulation of intracellular polyglutamated methotrexate is a slow process [20], which might explain this delayed response to MTX monotherapy. TNF inhibitors, however, often show an immediate onset of clinical improvement in the first weeks [21].

Furthermore, the investigators believe that reaching an inactive disease state in the early stage of arthritis (up to 2 years after the onset) may prevent the development of irreversible osteoarticular changes and reduce the future risk of disability since the earlier the treatment with biological preparations is started in an aggressive course of the disease, the more chances for the reversibility of pathological changes. In fact, the delay in identifying the optimal treatment at an early stage of disease can influence long-term joint damage [22].

When preparing novel clinical guidelines, experts should take into account a number of questions related to the identification of the optimal administration of biologics (monotherapy versus combination with non-biologic DMARD). The subsequent questions should address the optimal use of each biologic, taking into account that there might be cases for whom biologic monotherapy is acceptable due to adequate patient response, adverse events, or other aspects. In particular, the question ‘should ETA monotherapy versus ETA + non-biologic DMARD be recommended for patients with polyarticular JIA?’ is still open. Similar questions are also open for all anti-TNF drugs. Furthermore, a double-blind placebo-controlled study to compare the effectiveness of MTX vs ADA + MTX therapy has been published [23]. Ramanan et al. demonstrated that adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients receiving adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. In another recent study comparing different treatment regimens [24], it was shown that in the long-term treatment strategy, there was no significant difference in the rate of achieving inactive disease. Nevertheless, the authors show that ACR30 has suitabledynamics for a large proportion of children on combination therapy with etanercept at the beginning of treatment. In this study, the difference with methotrexate monotherapy at 3 months is approximately 20%, which is consistent with our results [24].

MTX is recommended as the first-line treatment in oligoarthritis persisting despite nonsteroidal anti-inflammatory drugs (NSAIDs) and intraarticular steroid therapy and in all patients with active polyarticular disease [4]. However, the question regarding shortening of the period before switching to biologics from MTX monotherapy to shorten the time to reach an inactive disease state and improve patient’s quality of life is still open. Although MTX is the first-choice drug in JIA, approximately 50% of patients fail to respond to it, and even in responders, the grade of remission is low [25, 26]. Given the time lag between MTX treatment initiation and the patient response (approximately 3 months), it would be particularly useful to determine a priori the probability of a beneficial therapeutic response [22]. According to the results of this study, ETA+MTX combination therapy allows patients to achieve remission sooner than MTX monotherapy. This fact makes it necessary to revise the timing of biologics treatment initiation in the current clinical guidelines.

Potential responders and non-responders to MTX should also be identified for optimizing the treatment regimens. The first attempts to identify predictors of methotrexate response were made a rather long time ago. In 2010, Vilca et al. analysed 563 patients from the PRINTO database [27]. All patients received MTX monotherapy for 6 months. The authors demonstrated that the most important predictors of non-response were as follows: disease duration > 1.3 years, ANA negativity, higher CHAQ disability index, and presence of right and left wrist activity. Hence, children with a severe disease course and long disease duration exhibit the worst response, even to long-term MTX monotherapy. In this study, we have confirmed these findings and additionally demonstrated that 94% of patients treated with ETA+MTX since treatment initiation responded to ETA treatment and achieved ACR30 during the first 12 weeks. However, only 60% of patients responded to the placebo+MTX treatment in the respective group, while the disease course was significantly milder in these patients according to joints with a limited range of motion, tender joints, the VAS score, and JADAS. Hence, MTX quickly provides relief only to children with a mild course of JIA, while ETA+MTX can help all children, regardless of disease severity. Data from the German BIKER registry from an even larger patient population of 731 JIA polyarticular JIA patients treated with MTX showed that a minimal response of a pedACR30 was reached by 77.4% at month 3 and by 83.1% of patients at month 12, while 43.1 and 65.9% of patients had a PedACR 70 response at months 3 and 12, respectively [28]. Thus, a minimal response was frequently already reached at month 3, while a stronger response to MTX treatment took usually longer to achieve. In multivariate analysis, the determinants for reaching PedACR 70 at month 12 were a disease duration of less than 1 year, a lower number of tender but a higher number of active joints and the presence of morning stiffness at baseline. Importantly, in the study of Albarouni et al. patients reaching a pedACR30 response at month 3 have a 4-fold increased and, thus, a significantly higher chance to reach pedACR70 at month 12 [28]. Patients who do not have a pedACR30 response at month 3, therefore, should not continue to receive the same treatment. In this study, we also collected safety data for MTX treatment vs anti-TNF + MTX. During the first 12 weeks of combination therapy, adverse events were reported in 17% of patients, while 33% of patients treated with placebo+MTX developed adverse events. Infectious adverse events were the most frequent AEs in both treatment groups.

Our study has a number of limitations. The groups being compared differed significantly at baseline in terms of a number of parameters, including disease duration and disease severity according to the CHAQ score. Despite randomization, patients in the ETA+MTX group had a higher age of JIA debut than patients in the Placebo+MTX group of initially combined therapy. This difference may be due to the multicentre character of the study since the 6 centres participating in the study were geographically widely scattered over the territory of the Russian Federation. The differences may be due to some population and ethno-genetic characteristics of JIA in children in different regions. JIA does not represent a single disease but is a group of very heterogeneous categories. Thus, greater differences than in adult studies including rheumatoid arthritis patients can be expected. Moreover, JIA compared to RA is a very rare disease, and only much smaller study samples can be studied. A younger age at disease onset may have influenced the response rate in the Placebo+MTX group. However, despite this possible advantage, the level of response in the first 12 weeks in the Placebo+MTX group was significantly lower. All other differences (higher swollen joint count, higher CPR level and JADAS-71 level) were also disadvantages for the primary combination group, which did not prevent ETA+MTX patients from demonstrating a higher level of response. Nevertheless, we performed a unique comparison of two different treatment schemes in a multicentre Russian prospective trial that can be compared to data for patients from other countries.

Our findings demonstrate that ETA+MTX combination therapy is a universal treatment regimen that can be used for patients with both mild and severe disease courses to quickly reduce inflammation and articular symptoms during the first 12 weeks of treatment. Only patients with a mild disease course respond quickly to MTX monotherapy. Patients treated with the ETA+MTX combination since treatment initiation reached an inactive disease state and remission more rapidly than patients for whom ETA was added only after they had failed to respond to MTX monotherapy. Hence, earlier addition of ETA to the treatment regimen shortens the time to achieve remission and improves patients’ quality of life. Both cohorts showed an acceptable safety profile.