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Methotrexate in Juvenile Idiopathic Arthritis: Answers and Questions

The first data on the use of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) were published 13 years ago1, and it has been 7 years since the randomized, double blind, placebo controlled trial by Giannini and co-workers established the efficacy of low dose (10 mg/m2) weekly MTX in JIA2. Recently, there has been an extensive clinical research effort aimed at defining more precisely the effectiveness and toxicity profile of this drug in JIA. As a result, MTX is now the therapeutic agent of choice for children with JIA who fail to respond adequately to the nonsteroidal antiinflammatory drugs (NSAID). After many years of clinical experience with this therapeutic agent, several aspects related to its optimal use and efficacy in JIA have been clarified. A number of questions, however, remain to be answered.

DOSE AND ROUTE OF ADMINISTRATION

In children with JIA, MTX therapy is commonly started at a dose of 10 to 15 mg/m2 and is administered weekly, either orally or parenterally (subcutaneously or intramuscularly). At these standard doses, the oral route is preferred by most pediatric rheumatologists because of its easier administration and greater child comfort; furthermore, there does not appear to be any advantage related to efficacy or safety with either the oral or parenteral method of administration3. Gastrointestinal (GI) absorption of MTX is best when the drug is given without food. Routine therapeutic monitoring of MTX after oral administration is not recommended because MTX blood concentrations have been shown to have wide interpatient and intrapatient variability4. At the standard dose regimen, 60 to 70% of patients with JIA benefit significantly from MTX therapy, with the maximum therapeutic effect usually becoming apparent 4 to 6 months after the beginning of treatment. The use of higher doses, up to 25-30 mg/m2/week, is worthy of consideration in children who have had only a partial response to the drug or have a more severe disease. Doses greater than 15-20 mg/m2 are administered parenterally because of the decreased oral bioavailability of the drug at higher doses. However, it is still unclear whether MTX acts in a dose-dependent manner in JIA. A multinational, controlled study coordinated by the Pediatric Rheumatology International Trials Organization (PRINTO) is under way to establish whether higher doses (30 mg/m2/week) of MTX are more effective than lower doses (15 mg/m2/week) in patients who are resistant to the conventional dose regimen.

Recent studies indicate that MTX may be an effective mode of therapy in children with JIA associated chronic uveitis complicated by cataract and glaucoma or resistant to topical corticosteroids5.

TOXICITY

In general, children tolerate MTX well. However, although serious toxicity is uncommon, a prevalence of adverse events as high as 42% has been reported3. Common side effects include GI toxicity (nausea, anorexia, stomatitis) and transient elevation of serum aminotransferase levels. There are occasional reports of alopecia, hematologic toxicity, headache, dizziness, fatigue, and mood changes in children with JIA. In some patients these complications may occur in the more generalized context of the so-called “post-dosing reaction,” a symptomatic reaction that occurs within 24 hours of a MTX dose and is usually characterized by malaise, fatigue, GI upset, and occasionally central nervous system manifestations. This bothersome complication, which is probably more common than previously realized, can lead to the child’s severe discomfort or even to permanent discontinuation of the drug. Various strategies for dealing with side effects have been proposed, including giving MTX at bedtime, changing to subcutaneous administration, giving antiemetics before MTX dosing, and lowering the dose of MTX. Because the pattern of GI side effects from MTX is similar to that of NSAID, withholding a dose of NSAID before and/or after MTX administration, or even changing the NSAID, may improve tolerance of the MTX–NSAID combination for a specific patient. It is unclear whether and to what degree the use of the higher MTX doses exposes the patient to increased risk of toxic events. Because folate deficiency has been thought to play an important role in the development of MTX side effects, folic or folinic acid supplementation has been proposed to reduce toxicity associated with MTX therapy. Studies in adult patients with rheumatoid arthritis (RA) have shown that folate supplementation is effective in lessening the frequency of MTX side effects without influencing the therapeutic benefit. A similar experience has been reported in children with JIA6. Among the rarer complications associated with MTX therapy, hypersensitivity pneumonitis and accelerated nodulosis have been described7. Although MTX has not been shown to be mutagenic or carcinogenic, there have been multiple reports of the development of lymphomas in MTX treated patients, including children with JIA8. Many of these tumors were Epstein-Barr virus positive. Although the rapid regression of lymphoproliferative disease after MTX withdrawal observed in some patients is suggestive of a pathogenetic role, it remains unclear whether this association represents an epiphenomenon, a natural consequence of the rheumatic disease, or a treatment related complication9.

The use of MTX has not been associated with alterations in fertility. However, because it is a powerful teratogen, teenage girls with childbearing potential should be given contraception counseling. No information exists on the indication, efficacy, or risk of vaccination in children with JIA taking MTX. In the absence of specific guidelines, live vaccines should be avoided.

One of the most significant potential longterm side effects of low dose MTX reported in adults is the development of liver fibrosis and cirrhosis. Alcohol use is the strongest risk cofactor, and the cumulative dose of MTX appears to increase the risk of developing liver fibrosis. However, the estimated frequency of cirrhosis or clinically decompensated liver disease in adults with RA after 5 years of MTX use is 1/100010. The risk of serious liver disease in the pediatric age is unknown. Although children may have fewer risk cofactors than adults, the dose of MTX per body surface area is greater in JIA than in RA. Since hepatotoxicity was initially the principal concern with respect to the use of MTX in patients with JIA, in the earlier MTX era it was recommended that liver biopsies be performed on the basis of cumulative drug doses. However, liver biopsy studies in children who had taken up to 4000 mg/1.73 m2 of MTX have shown that, although minor histologic abnormalities were common, none of the biopsy samples showed significant fibrosis (i.e., Roenigk grade IIIB or IV)11. Although these findings do not permit definitive conclusions due to the small sample size and the cross sectional nature of most studies, they suggest that the potential for longterm hepatic toxicity of MTX is minimal in JIA. The American College of Rheumatology (ACR) has issued guidelines for monitoring MTX hepatotoxicity in adults with RA based on the significant association of serial abnormalities of serum aminotransferases (defined as elevation above the upper limit of normal) and decreased serum levels of albumin during well controlled disease with the severity of liver histopathology12. These laboratory tests should be performed every 4 to 8 weeks. The validity of these guidelines has never been tested in JIA. In a recent study of 33 percutaneous liver biopsy specimens from 25 patients with JIA, an association between serial biochemical abnormalities (e.g., any elevation of AST and ALT or decrease in albumin beyond the normal range) with the presence of fibrosis, while never significant (i.e., Roenigk grade IIIA or less), was observed13. Although the relevance of this finding is limited by the retrospective nature of our study, the lack of pretreatment biopsies, and the fact that no biopsy showed severe fibrosis, it supports the usefulness of the ACR guidelines for pediatric patients. According to the guidelines, it has been suggested that liver biopsy be considered in JIA patients with > 40% abnormalities of the liver enzyme tests done in the course of a year13. Since it is clear that alcohol consumption is a major risk factor in the development of liver fibrosis, alcohol avoidance should be recommended in adolescent patients taking MTX. Moreover, it is our policy to perform hepatitis B and C serologic studies in all patients newly started with MTX.

WHEN TO START TREATMENT?

A common question regarding the use of MTX in children with JIA is when to initiate treatment. Longterm followup studies of JIA populations have shown that the disease is not benign and that radiographic joint damage is common and occurs early. Thus, the proportion of children with an unfavorable outcome is now estimated to be much greater than once believed. By investigating retrospectively the factors associated with the clinical response to MTX in 19 children with systemic onset JIA, we found that a favorable therapeutic outcome was associated with a shorter disease duration and a lower percentage of radiologic lesions at baseline14. Nevertheless, a rationale for timing MTX introduction is still hampered by our inability to predict the course and outcome in individual patients with JIA. We usually add MTX to the treatment regimen as early as 6 months after the disease onset in children with resistant polyarticular course JIA.

WHEN TO DISCONTINUE TREATMENT?

The issues of when, how, and by what criteria to discontinue MTX are critical for children with JIA. At present, there is no widely accepted definition for remission in JIA. Reported rates of remission in JIA treated with MTX vary from 6.9 to 45%; the average duration of MTX treatment until remission is around one year at a weekly dose of 10-15 mg/m2 7. Due to concerns from the earlier MTX era about the risk of longterm liver toxicity, in the past MTX was often discontinued shortly after complete disease control was achieved. However, a high frequency of relapse after MTX withdrawal among these patients was observed, particularly in those with oligoarticular onset and polyarticular course (extended oligoarticular subtype)15. At present, most investigators favor continuing MTX therapy longer after clinical remission is achieved. However, there are no guidelines to help clinical decision-making regarding length of MTX treatment after remission. Furthermore, it is not established whether the dosage and frequency of administration should remain stable or gradually decrease. Our current policy is to continue MTX at a weekly regimen and unchanged dosage for 6 months after the achievement of a sustained remission, and then to taper it until discontinuation by spacing the same weekly dosage further apart over an additional 6 months.

IS MTX EQUALLY EFFECTIVE IN THE DIFFERENT JIA ONSET TYPES?

JIA is a heterogeneous condition, and a different susceptibility to MTX treatment among its different onset types may exist. Past analyses of MTX efficacy by onset type have provided conflicting results. Moreover, the therapeutic response was evaluated by different criteria and seldom assessed at standard time points. In a retrospective study aimed at identifying potential predictors of MTX efficacy in a cohort of 80 children with JIA, we found that the extended oligoarticular subtype was the stronger predictor for both the short term clinical response and complete disease control. Patients with this subtype of JIA tended to experience earlier and more frequent relapse of their arthritis after MTX discontinuation16. These results suggest that MTX is more effective in the subset of JIA patients with the extended oligoarticular subtype.

IS MTX A DISEASE MODIFYING AGENT IN JIA?

Although the clinical efficacy of MTX in JIA is well established, it is still uncertain whether it has a disease modifying potential and thus is able to improve and sustain function and prevent or significantly decrease the rate of progression of structural joint damage. In a cohort of 29 patients with polyarticular course JIA of either systemic or polyarticular onset, we found that after 6 months of MTX therapy the mean functional index in responders decreased from 17 to 13 (p < 0.001), whereas in nonresponders it did not change from baseline17. Studies in adults with RA have shown that MTX is more effective in slowing radiographic bony destruction compared with other disease modifying antirheumatic drugs. Harel, et al18 were the first to examine the effects of MTX on radiologic progression in JIA by evaluating serial wrist carpal length in 23 patients. After a mean 2.5 years of MTX therapy, 11 of 17 responders had improved carpal length, whereas all 6 nonresponders had a progressive loss of carpal length. We also used carpal length to evaluate radiographic progression in 26 children with polyarticular course JIA after 12 and 24 months of treatment with MTX. Comparison of the responder and nonresponder groups from onset of treatment showed no statistically significant change in carpal length at 12 months, whereas at 24 months the carpal length was significantly more deteriorated in nonresponders in both the “better” wrist (p = 0.001) and the “worse” wrist (p = 0.005)19. Taken together, these data provide preliminary evidence that MTX acts as a disease modifying agent in JIA.

IS IT WORTH COMBINING MTX WITH OTHER SECOND-LINE AGENTS?

In adults with RA, MTX has been employed in combination with several other second-line drugs, including sulfasalazine, hydroxychloroquine, azathioprine, cyclosporine, and cyclophosphamide in patients who do not do well taking MTX alone. Although there are few reports on the use of combination therapies in children with JIA, this is standard practice for many pediatric rheumatologists, especially for MTX and sulfasalazine and MTX and cyclosporine20. Large scale, controlled trials are needed to establish whether these combinations will enhance MTX efficacy and to determine their potential for additive toxicity. Recent studies in adults with RA have provided encouraging results with the use of MTX in combination with the new anti-tumor necrosis factor molecules entanercept and infliximab.

In summary, methotrexate is an effective, well tolerated, and inexpensive medication for the treatment of patients with JIA. While it is still premature to state that MTX will change the longterm outcome in JIA, it has significantly changed the short and medium term outcome in many children with this disease. Further clinical research with the drug is needed to answer unresolved questions about its therapeutic use, alone or in combination, in JIA.

ANGELO RAVELLI, MD,
Dirigente Medico I livello;
ALBERTO MARTINI, MD;
Professor of Pediatrics,
Dipartimento di Scienze Pediatriche,
Università di Pavia,
IRCCS Policlinico San Matteo,
P. le Golgi 2, 27100 Pavia, Italy;
E-mail: amartini@smatteo.pv.it

Address reprint requests to Dr. Martini.

REFERENCES

1.Truckenbrodt H, Hafner R. Methotrexate therapy in juvenile rheumatoid arthritis: a retrospective study. Arthritis Rheum 1986;29:801-6.

2.Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. N Engl J Med 1992;326:1043-9.

3.Ravelli A, Gerloni V, Corona F, et al. Oral versus intramuscular methotrexate in juvenile chronic arthritis. Clin Exp Rheumatol 1998;16:181-3.

4.Ravelli A, Di Fuccia G, Molinaro M, et al. Plasma levels after oral methotrexate in children with juvenile rheumatoid arthritis. J Rheumatol 1993;20:1573-7.

5.Weiss AH, Wallace CA, Sherry DD. Methotrexate for resistant chronic uveitis in children with juvenile rheumatoid arthritis. J Pediatr 1998;133:266-8.

6.Ravelli A, Migliavacca D, Viola S, Ruperto N, Pistorio A, Martini A. Efficacy of folinic acid in reducing methotrexate toxicity in juvenile idiopathic arthritis. Clin Exp Rheumatol 1999;17:625-7.

7.Wallace CA. The use of methotrexate in childhood rheumatic diseases. Arthritis Rheum 1998;41:381-91.

8.Padeh S, Sharon N, Schiby G, Rechavi G, Passwell JH. Hodgkin’s lymphoma in systemic onset juvenile rheumatoid arthritis after treatment with low dose methotrexate. J Rheumatol 1997;24:2035-7.

9.Bleyer WA. Methotrexate induced lymphoma? J Rheumatol 1998;25:404-7.

10.Walker AM, Funch D, Dreyer NA, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis Rheum 1993;36:329-35.

11.Hashkes PJ, Balistreri WF, Bove KE, Ballard ET, Passo MH. The long-term effect of methotrexate therapy on the liver in patients with juvenile rheumatoid arthritis. Arthritis Rheum 1997;40:2226-34.

12.Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. Arthritis Rheum 1994;37:316-28.

13.Hashkes PJ, Balistreri WF, Bove KE, Ballard ET, Passo MH. The relationship of hepatotoxic risk factors and liver histology in methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr 1999;134:47-52.

14.Ravelli A, Ramenghi B, Di Fuccia G, Ruperto N, Zonta L, Martini A. Factors associated with response to methotrexate in systemic-onset juvenile chronic arthritis. Acta Paediatr 1994;83:428-32.

15.Ravelli A, Viola S, Ramenghi B, Aramini L, Ruperto N, Martini A. Frequency of relapse after discontinuation of methotrexate therapy for clinical remission in juvenile rheumatoid arthritis. J Rheumatol 1995;22:1574-6.

16.Ravelli A, Viola S, Migliavacca D, Ruperto N, Pistorio A, Martini A. The extended oligoarticular subtype is the best predictor of methotrexate efficacy in juvenile idiopathic arthritis. J Pediatr 1999;135:316-20.

17.Ravelli A, Viola S, Ramenghi B, et al. Evaluation of response to methotrexate by a functional index in juvenile chronic arthritis. Clin Rheumatol 1995;14:322-6.

18.Harel L, Wagner-Weiner L, Poznanski AK, Spencer CH, Ekwo E, Magilavy DB. Effects of methotrexate on radiologic progression in juvenile rheumatoid arthritis. Arthritis Rheum 1993;36:1370-4.

19.Ravelli A, Viola S, Ramenghi B, Beluffi G, Zonta L, Martini A. Radiologic progression in juvenile chronic arthritis patients treated with methotrexate. J Pediatr 1998;133:262-5.

20.Wallace CA. On beyond methotrexate treatment of severe juvenile rheumatoid arthritis. Clin Exp Rheumatol 1999;17:499-504.



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