The German Methotrexate Registry is sponsored by Wyeth Biopharma, which was acquired by Pfizer in October 2009.
The German Methotrexate Registry has been collecting data concerning the efficacy and safety of methotrexate (MTX) treatment since 2005. The aim of this retrospective analysis is to compare oral and parenteral MTX treatment regarding efficacy and safety.
Inclusion criteria were diagnosis of juvenile idiopathic arthritis, MTX treatment for at least 6 months, a consistent route of administration of MTX, and no previous or concomitant treatment with biologic agents. Efficacy was measured by the American College of Rheumatology (ACR) pediatric (Pedi) criteria. Primary outcome was efficacy defined as the number of patients reaching ACR Pedi 30 improvement criteria after 6 months of treatment. Secondary outcome criteria were the ACR Pedi 50 and Pedi 70 criteria at 6 and 12 months, respectively. Analyses were performed with the intent-to-treat population.
Of the 411 eligible patients, 259 (63%) received oral MTX and 152 (37%) received subcutaneous MTX. In both patient groups, a comparable weekly dose of MTX (0.4 mg/kg versus 0.42 mg/kg) was used, and a comparable number of patients received concomitant steroids. The primary outcome in both treatment groups was that a comparably high number of patients showed a clinical response according to the ACR Pedi 30 score after 6 months of treatment (73% versus 72%; P = 0.87). Twenty-two percent of patients with oral therapy and 27% with subcutaneous therapy had at least 1 documented adverse event. Discontinuation of treatment was observed in both groups with equal frequency, while significantly more patients with subcutaneous application discontinued MTX because of adverse events (11% versus 5%; P = 0.02).
In this retrospective analysis, parenteral MTX was not superior to oral administration regarding efficacy and tolerability.
Juvenile idiopathic arthritis (JIA) is a collective term for different entities of diseases with arthritis starting before the age of 16 years (1). With an incidence of 19.8 per 100,000 children age <16 years, JIA is the most common chronic inflammatory disease in childhood and can lead to severe disability (1–4).
Pharmacomedical treatment of JIA consists of nonsteroidal antirheumatic drugs mainly for symptomatic relief and disease-modifying antirheumatic drugs (DMARDs). Of the latter group, methotrexate (MTX) has become a cornerstone in the treatment of polyarticular JIA patients. Its efficacy has been demonstrated in a randomized controlled trial 2 decades ago (5). MTX has been studied in further controlled clinical trials and emerged to be the most common first-line DMARD treatment according to several national treatment guidelines (6–10).
In these studies, MTX has shown an acceptable safety profile, although vomiting and nausea are especially limiting its use in children (11). The precise mechanism of action of MTX remains unclear, although it may inhibit the proliferation of cells via inhibition of de novo synthesis of purine and pyrimidine, which is essential for synthesis of DNA and RNA. The antiinflammatory effects of MTX are mediated by an increase of adenosine release (12).
Usually MTX is applied once weekly. There are 2 routes of application, oral or subcutaneous. Pediatric patients especially may fear the injections, which can be painful. This may pose a significant burden for patients and their parents. If parents feel unable to give the injections themselves, more consultations of physicians or health care professionals may be the result. Until now there is no consensus as to which route of administration is to be preferred. While a controlled prospective study comparing oral versus parenteral administration in adult patients with rheumatoid arthritis (RA) showed significantly higher American College of Rheumatology (ACR) 20% and 70% improvement criteria response rates in patients with parenteral MTX, this remains to be analyzed in JIA patients (13). However, the data suggest a number needed to treat of 12.5 for adult RA patients for 1 patient to benefit from subcutaneous MTX over oral MTX. In JIA patients, 2 studies reported the successful use of parenteral MTX treatment in patients who failed oral treatment (7, 14). However, there is still limited information about efficacy and safety of oral versus subcutaneous MTX for the treatment of JIA available in the literature. Comparative prospective studies are especially needed.
The aim of this study was to compare efficacy of oral versus parenteral MTX treatment and to assess differences in side-effects profiles in a multicenter cohort of children with JIA.
Significance & Innovations
The question of how to start treatment with methotrexate (MTX) in children with juvenile idiopathic arthritis (JIA), orally or via subcutaneous injections, is of great importance. There is no common consensus. Especially for pediatric patients, the injections can be painful, may pose a significant burden for the patients and their parents, and may result in more consultations of physicians or health professionals if parents feel unable to give the injections themselves.
The observation made in our large registry is that there is no major difference in efficacy between oral and parenteral application of MTX. Moreover, we were not able to observe a better tolerability of parenteral MTX.
The aim of this study is to underline the urgent need for a randomized controlled clinical trial, which may or may not demonstrate superiority of parenteral MTX. Only then can parenteral MTX be recommended for treatment of children with JIA instead of oral application..
PATIENTS AND METHODS
This is a multicenter study of consecutive children diagnosed with JIA and enrolled in the German Methotrexate Registry from October 1, 2005 until June 30, 2009. The registry has been approved by the ethical committee of Martin Luther University, Halle-Wittenberg, and the ethical committee of the Aerztekammer Nordrhein, Duesseldorf.
Patients were included in this study if they had a diagnosis of JIA according to the published criteria (1), had newly started treatment with MTX, and were documented in the registry. Only those patients who had been treated with MTX for at least 6 months were analyzed. Exclusion criteria were a history of or concomitant therapy with biologic agents. The route of application was decided by the treating physician. Since no data were collected for the cause of change of the route of MTX application, patients who had a change of route of administration of MTX during the observation period were excluded from the analysis.
The German Methotrexate Registry has been collecting data prospectively concerning efficacy and safety of long-term treatment with MTX since 2005. The subject's/parent's written consent was obtained before enrollment, if the physician decided to start treatment with MTX. Before start of treatment with MTX, data were collected from patients/parents and from medical documents, and patients were assessed clinically. Laboratory results, which are done routinely, were documented.
The following data were collected at baseline: age at start of treatment, sex, duration of disease, JIA subtype, previous medical history, previous and current treatments, date of first dose of MTX, prescribed dose of MTX, clinical assessment including weight, height, joint assessment, general examination, physician global assessment of disease activity, and parent/patient global assessment of overall well-being, with measures being a 10-cm visual analog scale (VAS), Childhood Health Assessment Questionnaire (C-HAQ), erythrocyte sedimentation rate (ESR), and C-reactive protein level. At 3 and 6 months after the start of therapy and then every 6 months the following data were collected: dose of MTX, missed doses of MTX, concomitant treatment, adverse events (AEs), and clinical and laboratory tests as described above. In case of discontinuation, the date of the last dose of MTX and reasons for withdrawal, if applicable, were documented. The reasons were requested as intolerance (AEs), inefficacy, remission, or other reasons. For the latter, details were recorded. Discontinuation of treatment due to “inefficacy” was not judged or predefined by the registry. More than 1 reason for discontinuation of treatment was possible.
Efficacy was assessed with the ACR pediatric (Pedi) 30, 50, and 70 improvement criteria, including the German C-HAQ, after 6 and 12 months of therapy (15–17). These core set parameters consisted of 1) physician global assessment of disease activity (10-cm VAS); 2) parent/patient global assessment of overall well-being (10-cm VAS); 3) the C-HAQ, a measure of physical function; 4) the number of joints with active arthritis, defined by the presence of swelling or, if no swelling is present, the limitation of motion accompanied by pain, tenderness, or both; 5) the number of joints with limited range of motion; and 6) the ESR. The ACR Pedi 30 was reached if there was an improvement of ≥30% in at least 3 of 6 core variables, with no worsening of >1 of the remaining variables by >30%. Patients were also evaluated for improvement of ≥50% or ≥70% improvement in at least 3 of 6 core variables, with no worsening of >1 of the remaining variables by >30% (ACR Pedi 50 and 70) (16). Nonresponders were defined as patients not reaching at least a ACR Pedi 30 response or patients who discontinued treatment due to inefficacy or starting on etanercept.
Primary outcome was efficacy of treatment with MTX defined as the percentage of patients with at least an ACR Pedi 30 score at 6 months of MTX treatment. Secondary end points were efficacy defined as the percentage of patients reaching ACR Pedi 50 and 70 scores at 6 months and ACR Pedi 30, 50, and 70 at 12 months of treatment. Safety was defined as the number of patients with AEs and the number of withdrawals.
An AE was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom, or disease that occurred during MTX treatment. Serious AEs were defined as events that were fatal or life threatening, resulted in a persistent or significant disability or incapacity, required prolonged inpatient hospitalization, or led to a congenital anomaly or birth defect. Additionally, the frequency of AEs was analyzed in patients with folic acid supplementation and compared to those without.
Demographic and baseline characteristics were summarized by descriptive statistics. Efficacy and safety analyses were performed in the intent-to-treat population, tests were 2-sided, and P values less than 0.05 were considered statistically significant. Patients who discontinued MTX treatment or received additional biologic agents, such as etanercept, during the first 6 months were labeled as nonresponders. Frequencies were compared using the chi-square test or Fisher's exact test as appropriate. Improvement of continuous disease activity parameters was compared using the t-test or Mann-Whitney U test. Since the reasons for choice of application are not known, we tested all baseline variables for a bias on the application with bivariate tests (parametric or nonparametric). To assess whether baseline parameters with an influence on treatment option confound the results, we performed a logistic regression analysis with outcome at 6 months, including significant baseline variables from the bivariate tests and choice of application. Data were entered in an Access 2003 database and analyzed with Excel 2003 (Microsoft). Comparative statistics were analyzed by SPSS, version 19.
A total of 1,066 JIA patients were included in the German Methotrexate Registry from October 1, 2005 until December 31, 2009. Of these, 609 patients had at least 6 months of MTX treatment with no concomitant use of biologic agent therapies. The inception cohort consisted of 411 patients, who did not switch the route of MTX administration during the first 6 months. While 104 patients changed from oral to subcutaneous application, 85 patients switched from subcutaneous to oral treatment. Of the 411 eligible patients, 259 patients received oral MTX exclusively and 152 patients received subcutaneous MTX exclusively (Figure 1). Both patient groups were comparable, with approximately two-thirds being female and a median age of 10 years (Table 1).
Table 1. Clinical and demographic characteristics of 411 patients at the start of MTX treatment, according to their route of application*
Patients taking oral MTX (n = 259)
Patients taking subcutaneous MTX (n = 152)
Values are the number (percentage) unless indicated otherwise. MTX = methotrexate; IQR = interquartile range; JIA = juvenile idiopathic arthritis; RF = rheumatoid factor.
Age, median (IQR) years
MTX dosage, median (IQR) mg/kg/week
Folic acid supplementation
Steroids at start of MTX therapy
Patients receiving triamcinolone, hexacetonide, or acetonide joint injections
Psoriasis and arthritis
Disease duration, median (IQR) years
Disease activity parameters at baseline.
At the beginning of MTX treatment there were no significant differences in active joint counts, number of joints with limited range of motion, and C-HAQ scores between the 2 cohorts. Patients with subcutaneous MTX treatment had significantly higher values for physician global assessment of disease activity, parent/patient global assessment of overall well-being, and ESR (Table 2). Also, duration of disease differed significantly with 1.1 years compared to 0.8 years. However, this was not noticeable in regression analysis. In both groups, persistent oligoarthritis was the predominant JIA subtype (36.1% versus 28%). Patients with seropositive polyarthritis received subcutaneous MTX more frequently (Table 1).
Table 2. Disease activity parameters at months 0 and 6 for patients receiving oral and subcutaneous MTX*
Values are the median (interquartile range) unless indicated otherwise. MTX = methotrexate; VAS = visual analog scale; C-HAQ = Childhood Health Assessment Questionnaire.
Mean improvement: the mean of the differences from 0–6 months of the respective parameter.
Number of active joints
Number of joints with limited range of motion
Parents' global assessment (VAS, range 0–100)
Physician's global assessment (VAS, range 0–100)
C-HAQ disability index (range 0–3)
Erythrocyte sedimentation rate, mm/hour
Dose of MTX was comparable in both groups. There were no significant differences in concomitant therapy with steroids (both systemic and intraarticular) between patients treated orally or subcutaneously. Significantly more patients in the oral group received folic acid (46% versus 32%; P = 0.002), but regression analysis did not show an influence of this fact on the outcome (Table 1).
Since the reasons for choice of application were not known, there was a possibility of confounding by indication. To assess whether the baseline parameters with an influence on treatment option confound the results, we performed logistic regression analysis with ACR Pedi outcomes at 6 months, including baseline variables and application. The analysis showed no influence of MTX application on ACR Pedi 30, 50, and 70 scores, but indeed showed a significant influence of baseline physician global assessment score (P < 0.001 on ACR Pedi 30, 50, and 70) and baseline diagnosis of seropositive polyarthritis (P = 0.007 on ACR Pedi 70), besides influences of other nonbaseline factors. Regarding efficacy, after 6 months of treatment with MTX, a significant improvement in all disease activity parameters was observed in both groups (Table 2), with no significant differences between the 2 groups.
Primary and secondary end points.
ACR Pedi 30 response after 6 months of treatment was reached in 188 (73%) of 259 patients in the oral administration group and in 110 (72%) of 152 patients in the subcutaneous administration group (P = 0.87) (Figure 2). For secondary end points, ACR Pedi 50 and 70 responses after 6 months of MTX therapy were observed with a similar frequency in both groups. In 66% of the patients in the oral group (n = 171) and in 69% of the patients in the subcutaneous group (n = 105), a response according to ACR Pedi 50 scores was observed (P = 0.59). An ACR Pedi 70 score was reached in 51% of patients (n = 131) with oral MTX and in 53% of patients (n = 80) with subcutaneous MTX (P = 0.98) (Figure 2). In both groups, 27% of patients were nonresponders at 6 months of either oral or subcutaneous MTX treatment. When comparing oral and subcutaneous administration at 3 months and 12 months of treatment with MTX, no significant differences in ACR Pedi 30, 50, and 70 scores occurred in our cohort (Figure 2).
Patients with polyarticular disease.
In our cohort, 83 patients on oral MTX and 65 patients on subcutaneous MTX had a polyarticular course of JIA (seronegative and seropositive polyarthritis and extended oligoarthritis). Separate analysis of these patients showed no differences in the frequency of ACR Pedi 30, 50, or 70 responses after 6 months of MTX therapy. Ninety-two percent of patients in the oral group and 84% of patients in the subcutaneous group reached ACR Pedi 30 scores. In the oral group, 83% of patients showed ACR Pedi 50 responses, and 62% of patients reached ACR Pedi 70 scores. In the subcutaneous group, an ACR Pedi 50 response was observed in 82% of patients, and an ACR Pedi 70 score was observed in 66% of patients.
Patients with oligoarticular disease.
A diagnosis of persistent oligoarthritis was documented in 94 patients taking oral MTX and in 42 patients taking subcutaneous MTX. With 67% of patients in the oral group and 83% of patients in the subcutaneous group, ACR Pedi 30 scores were reached slightly more frequently in the subcutaneous treatment group. ACR Pedi 50 and 70 scores were documented in 64% and 51% of patients, respectively, in the oral group, and in 76% and 54% of patients, respectively, in the subcutaneous group. None of the differences were significant. The number of patients with the JIA categories of systemic arthritis, psoriatic arthritis, and enthesitis-related arthritis were too small to be evaluated separately.
In the evaluated group, 141 AEs occurred during the course of treatment with MTX. Seventy-six AEs were documented in 58 patients taking oral MTX. In the subcutaneous MTX group, 41 patients experienced 65 AEs (Table 3). Up to 6 AEs occurred in a single patient. Twenty-two percent of patients in the oral group and 27% of patients in the subcutaneous group had at least 1 documented AE (P = 0.29). When comparing the safety data of patients who changed the route of application, there were no differences between those treated first with oral MTX switching to subcutaneous administration, and vice versa, regarding the number or the type of AEs. In the cohort starting with oral MTX, 15 AEs were reported in 104 patients. In the cohort starting with subcutaneous MTX, 15 AEs were reported in 85 patients. Nausea was reported in 4 of 104 patients started on oral MTX therapy and in 5 of 85 patients started on subcutaneous MTX therapy. There were only single cases of other AEs.
Table 3. Adverse events (AEs) and severe AEs in patients taking oral and subcutaneous MTX*
Oral administration of MTX (n = 259 patients, 383.5 total PY)
Subcutaneous administration of MTX (n = 152 patients, 217 total PY)
AEs in 58 patients (n = 76)
AEs per PY
AEs in 41 patients (n = 65)
AEs per PY
MTX = methotrexate; PY = patient years on treatment.
Elevated liver enzymes
Abnormalities in blood count
Elevated body temperature
Elevated serum creatinine
Acute lymphatic leukemia
Safety and folic acid supplementation.
Of the total 411 patients in both groups, 168 patients received prophylactic folic acid supplementation. In these 168 patients, 73 AEs were documented. In the 243 patients without folic acid supplementation, 68 AEs were documented. There were no significant differences comparing those patients who had at least 1 documented AE with those who did not have any AEs, in either the oral or subcutaneous group.
Of the 411 patients evaluated, 89 patients discontinued MTX treatment. Most of these patients discontinued treatment because of remission of disease. Ten patients in the oral group and 9 patients in the subcutaneous group discontinued MTX therapy prematurely during the first 6 months of treatment. Very few patients discontinued treatment due to treatment failure, but significantly more patients with subcutaneous application discontinued MTX because of AEs (16 [11%] of 152 versus 12 [5%] of 259; P = 0.02). The detailed list of reasons for discontinuation of therapy is shown in Table 4. In our cohort, only 3 patients in the oral group and 2 patients in the subcutaneous group started on etanercept during the observation period.
Table 4. Reasons for discontinuation of MTX therapy in patients taking oral and subcutaneous MTX*
Oral MTX (n = 259)
Subcutaneous MTX (n = 152)
Values are the number (percentage) unless indicated otherwise. In some patients, more than 1 reason for discontinuation of treatment was given, resulting in overlapping of respective categories. MTX = methotrexate.
Adverse events total
The frequency of discontinuation was not in general influenced by folic acid supplementation. Thirty-six (21%) patients with folic acid supplementation discontinued MTX treatment, while 53 (22%) patients without folic acid supplementation stopped MTX treatment. In the patient group receiving oral MTX, 19 (16%) of 120 patients of those with folic acid and 33 (24%) of 139 patients of those without folic acid discontinued treatment. This difference was not significant. However, in the subcutaneous MTX group, 17 (35%) of 48 patients with folic acid supplementation discontinued treatment, but only 20 (19%) of 104 patients without folic acid supplementation discontinued treatment. This difference was significant (P = 0.042).
Treatment with either oral or parenteral MTX appears to lead to a comparable improvement in JIA patients. No differences in the ACR Pedi 30, 50, or 70 scores were observed whether patients received oral or subcutaneous MTX.
In studies in adult patients with RA, parenteral administration of MTX was superior to oral administration of MTX in terms of efficacy and bioavailability (13, 18). For JIA patients, studies reported the successful use of parenteral treatment in nonresponders to oral MTX treatment, but there are no controlled comparative studies, only open-label studies available (7, 14). In the latter studies, the superiority of the parenteral application may have been affected by the prolongation of treatment, as well as by other effects seen in open studies. In our cohort, we could not demonstrate an advantage of parenteral MTX over oral application in the ACR Pedi 30, 50, or 70 scores.
In the present study, disease activity parameters at the start of MTX treatment of both the oral and the subcutaneous group were comparable, except for both global assessment of disease activity on a VAS by parent/patient and physician and for the ESR. Patients of the subcutaneous group had significantly higher values here. The mean improvement of these parameters showed no difference when compared with the oral group. The more specific and objective parameters (C-HAQ, active joint count, and number of joints with limited range of motion) showed no significant differences. Of all baseline confounders of choice of application, only the parameters of physician global assessment and diagnosis of seropositive polyarthritis had a significant influence on ACR Pedi outcomes in the regression analysis. Physicians may have treated patients they assessed as severely diseased with subcutaneous MTX rather than with oral MTX. However, when looking at less subjective criteria, such as active joint counts or concomitant therapy, we found no significant differences between the 2 groups.
Regarding safety, patients with subcutaneous MTX treatment showed a higher rate of AEs without reaching significant differences. However, significantly more patients with parenteral MTX discontinued treatment for reasons of AEs. Premature discontinuation of therapy was similarly frequent in both groups.
Patients with oral MTX therapy received supportive folic acid treatment significantly more often. The reason might be that physicians more frequently expect the occurrence of gastrointestinal AEs and elevation of liver enzymes due to oral application of MTX and therefore use folic acid preemptively. Beneficial effects of folic acid treatment have been described previously (19, 20). However, treatment with folic acid did not affect outcome. Finally, regarding tolerability, oral application of MTX seems to have a slight advantage over subcutaneous application.
There are a number of limitations to our study. First of all, it is an open and nonrandomized study. Furthermore, we cannot draw conclusions about compliance. It is unlikely that compliance is higher in patients with oral administration. According to our opinion, it seems easier to forget or to deny taking a tablet than to miss an injection, which in the daily practice is given by the parents. A number of patients changed from oral to subcutaneous application or from subcutaneous to oral MTX. The reasons for this were not recorded systematically. The incidence of AEs did not seem to play a role. Therefore, we excluded these patients from our analysis. Concomitant therapy with steroids may have had an influence; patients in the subcutaneous group received intraarticular and systemic steroids slightly more frequently, but the difference was not significant. Finally, the reasons for starting oral or subcutaneous MTX in single patients are not deducible from our data. While some centers predominantly use one route of administration, others use oral and subcutaneous MTX equally frequently. This may pose a bias to our data. We found several significantly different baseline characteristics regarding choice of application. However, in regression analysis, only “physician global assessment scores” and “diagnosis of seropositive polyarthritis” showed an influence on ACR Pedi outcome, but they did not affect the results of our study with respect to application mode.
In this retrospective analysis of data from the German Methotrexate Registry for the long-term treatment of JIA with MTX, we could not demonstrate that subcutaneous MTX was superior to oral MTX regarding efficacy and tolerability. The often unpopular and more expensive parenteral application could probably be spared without consequences. For definite recommendations for the route of application of MTX treatment, controlled randomized prospective studies are required in children and juvenile patients.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Klein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Horneff.
Acquisition of data. Klein, Foeldvari, Ganser, Urban, Horneff.
Analysis and interpretation of data. Klein, Kaul, Horneff.
ROLE OF THE STUDY SPONSOR
The registry was founded by an unrestricted grant from Pfizer (formerly Wyeth Pharma). Pfizer had no influence on study design, data analysis, and/or manuscript writing. The submitted manuscript has not been discussed with the sponsor. Publication was not established as a contractual part of the grant.
The German Etanercept Registry acknowledges the contributions of the German and Austrian Paediatric Rheumatology Collaborative Study Group (PRCSG). The following members of the PRCSG participated in data collection: Girschick H., Würzburg; Linnemann K., Greifswald; Hühn R., Halle; Kuester R. M., Bad Bramstedt; Minden K., Berlin; Möbius D., Cottbus; Onken N., Bremen; Peitz J., Stuttgart; Quietzsch J., Plauen; Roth J., Berlin; Rothmeier A., Berlin; Sallmann S., Dresden; Schofer O., Neunkirchen; Stritzke J., Bremen; Thon A., Hannover; Tzaribachev N., Tübingen.