Methotrexate efficacy, but not its intolerance, is associated with the dose and route of administration

Subcutaneous MTX weekly dose around 15 mg/m2 is associated not only with a high response rate within the first 12 months of treatment, but also with a relatively low rate of significant adverse effects that would lead to the treatment termination. It allows early recognition of MTX non-responders and addition of biologic therapy. Sustainability of therapeutic effect and longer-term evolution of adverse events will be addressed by an ongoing extension of the study.

Low-dose weekly methotrexate (MTX) has been commonly used in the treatment of juvenile idiopathic arthritis (JIA). It is recommended as a first-line disease-modifying drug for disease unresponsive to nonsteroidal (NSAIDs) and/ or intraarticular corticosteroids. Differences in drug dosing and route of administration as well as in the method of efficacy assessment hamper inter-study comparisons. Among factors influencing inter-patient heterogeneity of treatment response, polymorphisms of genes involved in MTX metabolic pathways, disease phenotype and its previous duration and several biomarkers have been reported. Moreover, factors related to MTX absorption and kinetics have also been shown to influence treatment efficacy. Evaluation of the presence, type and severity of drug adverse events forms a natural part of therapeutic monitoring. Low-dose MTX has a variety of adverse effects. These include features of MTX ant proliferative effect which are mostly related to its post-dose concentrations. MTX affects rapidly dividing cells of gastrointestinal (GI) tract causing nausea and/or vomiting and bone marrow leading to cytopenia. Mechanisms of hepatic and central nervous system (CNS) toxicity are more complex and include elevation of liver enzymes, headaches and behavioral changes. Patients report presence of gastrointestinal symptoms or behavioral changes (cry, irritation, refusal to take the drug) already before or at the time of MTX administration (anticipatory intolerance) or even when just thinking about it (associative intolerance). They appear to be more commonly associated with parenteral route of MTX administration and often lead to precautious termination of otherwise safe and effective treatment. Therefore, monitoring of MTX adverse events requires not only regular blood tests for hepatic and marrow toxicity, but also directed questioning to detect subjective complaints.

Rationale behind research:

There is a lack of published evidence on the importance of methotrexate (MTX) dose and route of administration on both its efficacy and adverse events in children with Juvenile Idiopathic Arthritis.

Objective:

To document the clinical practice based on the treat-to-target approach in order to support the concept that better therapeutic effect achieved with an optimal dose of parenteral MTX is associated with clinically acceptable adverse effects comparable to those reported for oral treatment.

Study outcomes

Assessment of treatment efficacy: Treatment effect was evaluated by using two standardized methodologies for JIA activity assessment: ACR Pedi (The American College of Rheumatology) and JADAS (the Juvenile Arthritis Disease Activity Score). ACR Pedi uses core-set of 6 disease activity variables (active joint count, limited joint count, physician global assessment of disease activity, parent/patient global assessment of the patient's well-being, Childhood Health Assessment Questionnaire and ESR/CRP) on 2 distinct occasions resulting in defined improvement rates of ACR Pedi 30, 50, 70 and 90. These rates are defined as improvement of at least 3 out of 6 variables by a minimum of 30, 50, 70 or 90% and no more than one of the resulting ones deteriorating by more than 30%. Good clinical response to MTX was defined as reaching the minimum of ACR Pedi 70. JADAS is a numeric score resulting from the values of 4 measures: active joint count (from 10, 27 or 71 joints), physician's global assessment of disease activity (10 cm VAS), parent/patient global assessment of overall well-being (10 cm VAS) and normalized ESR rate (0–10). JADAS-71 (score range 0–101) was chosen for this study. Additionally, disease state at 6 and 12 months was assessed according to the JADAS cutoff values as inactive disease (≤1) or minimally active disease (≤2 for oligoarthritis and ≤3.8 for polyarthritis) and high disease activity (4.2 for oligoarthritis and 10.5 for polyarthritis). Complete treatment response was also defined applying the Wallace criteria as the presence of inactive disease (clinically inactive disease, CID). CID is defined by an absence of active synovitis or other active JIA features, normal ESR or CRP, the lowest possible physician global evaluation of disease activity and absence of significant morning stiffness (duration ≤15 min) 

Assessment of MTX treatment adverse events: MTX adverse events were divided into toxicity and intolerance. Toxic adverse events were further assessed as measurable toxicity (increase of at least one liver transaminase above 2- times of upper normal limit (ULN) or significant cytopenia or anemia) and patient-reported toxicity defined as patient complaints developing after MTX administration (gastrointestinal symptoms - abdominal pain, nausea, vomiting, oral ulcers, injection site reaction). Patient reported symptoms were captured at every visit using the Czech adaptation of the Methotrexate Intolerance Severity Score (MISS), which defines MTX-intolerant patient by the presence of at least 6 out of 36 points with at least 1 point on anticipatory and/or associative and/or behavioral symptoms

• Time Points: Every 3 months for 1 year
  

Outcomes

• MTX Therapy: In 45 patients (81,8%) MTX was started as once weekly subcutaneous injection, 10 patients received oral tablets. Parenteral MTX was administered in the median weekly dose of 14.4 mg/m2 (IQR 13.3; 15.9), oral MTX dose was 11.7 (8.3; 12.5) (p < 0,001). MTX dose (median (IQR)) was increased from 12.1 (11.1; 13.7) mg/m2 at study entry to 14.9 (13.6; 15.6) and 13.8 (12.4; 15.8) mg/m2 at 6 and 12 months, respectively, in 18 patients (32.7%). In 20 children (36.4%) it was decreased from 14.3 (12.4; 16.1) to 13.7 (12.2; 15.2) and 10.5 (8.8; 12.8) mg/m2 at 6 and 12 months, respectively. Other treatment modifications included change in the route of administration (n = 13; 23.6%), withdrawal (n = 5; 9.1%), addition of biological therapy (n = 14; 25.5%).
• Treatment efficacy and disease activity assessments: MTX therapy was effective in the level of ACRpedi70 and 90 in 50.9 % and 42.9 % of patients at month 6 and in 70.9 % and 63.6 % after 12 months of the treatment. Patients who received biologics (n = 14) were considered non-responders to MTX from the time point of starting the biologic including 4 children who achieved CID after biologic medication was added to MTX who were excluded from the evaluation of disease inactivity. Total of 61.8 % patients reached low disease activity according to published JADAS cutoff values for oligo and polyarthritis. Neither the rate or extent of therapeutic response were influenced by JIA onset subtype or by the route of MTX administration.
• MTX toxicity and intolerance: During the 12-month follow-up measurable toxicity of MTX was recorded in 8 patients (15.4 %): elevation of transaminases in 7 patients and cytopenia in 1 patient. In 3 cases these adverse events led to MTX withdrawal while in the remaining 5 children results normalized after the short treatment interruption or MTX dose reduction. None of the patients reported significant oral ulcers or injection site reaction. Only 11/55 patients (20 %) reported no adverse events throughout the observational period.

Intolerance (MISS ≥ 6) slowly developed during the initial months of the treatment and was present in the maximum of 25.5 % of patients at 6 months and remained relatively stable thereafter (30.6 % at 12 months). There were no serious adverse events (e.g. infections, pulmonary toxicity) that would require hospital admission throughout the study period. Management of intolerance included change in the dose and/or route of administration, education and counselling.

This study showed subcutaneous MTX weekly dose around 15 mg/m2 is associated not only with a response rate of ACRpedi 70 in over 70% of patients, but also with a very low rate of significant adverse effects that would lead to the treatment termination. In this cohort of 55 patients starting MTX only 10 (18.2 %) received oral tablets. Treatment response at 6 and/or 12 months is expressed by the percentage of patients achieving ACRpedi70 and/or CID. Proportion of MTX responders at 6 months is similar across most of the studies ranging from 38 to 56% of patients, similar to results in present study.

Multiple studies have dealt with potential biomarkers of response to MTX that could inform therapeutic decision-making and lead to early introduction of other treatments in suspected non-responders, reviewed by Dijkhuizen. In this study, attempt has been made to distinguish toxic adverse events limited to laboratory changes and post-dose GI symptoms from the intolerance featuring GI symptoms around MTX administration (anticipatory) and when thinking about MTX (associative) using a previously validated scoring system MISS. Behavioral symptoms at MTX administration were also systematically recorded. Proportion of patients who featured measurable toxic adverse events of transaminase elevation and/or cytopenia was similar to published series and was mild and easy to manage in most cases. Presence of patient-reported GI toxicity and intolerance and behavioral symptoms were frequent. MTX intolerance (MISS ≥ 6) in at least one visit during 12 months of treatment was recorded in 45.5% patients. This finding does not support the presence of direct relationship between MTX dose and route of administration and its intolerance. Severity of MTX intolerance is difficult to assess due to subjective nature of patient-reported symptoms. Therefore, it is believed that an impact of reported events on treatment itself should serve as a main measure of their clinical significance.