Juvenile dermatomyositis (DM) is a chronic multisystem disease of presumed autoimmune origin that primarily affects skin and muscle. In western populations, the incidence of juvenile DM is ∼2–3 per 1 million children per year (1–3). Although the outcomes of juvenile DM have improved over the last few decades, the disease is still associated with significant morbidity in a proportion of patients (4, 5). For many patients, juvenile DM follows a chronic course. According to a recent retrospective multicenter Canadian study of children with juvenile DM, 35% of the children (23 of 65) were still receiving medication for persistent disease activity after a median followup of 7 years (5).
No prospective randomized study has shown the efficacy of any immunosuppressive agent for the treatment of juvenile DM. The mainstay of therapy for juvenile DM has been long-term corticosteroid treatment, which, although efficacious, is associated with significant side effects. The standard approach to treatment of juvenile DM has been use of high doses of oral corticosteroids, with slow tapering over at least 2 years (6). The major limitations of this treatment are side effects and, in some patients, incomplete response.
The major side effects of corticosteroids include growth delay, osteoporosis, avascular necrosis, cataracts, and hypertension. In 2 studies (7, 8), side effects of corticosteroids were observed in 32–41% of adult patients with DM or polymyositis. Although the relationship between cumulative doses of corticosteroids and these side effects remains unclear, in general the side effects of corticosteroids are thought to be related to the dose and duration of therapy. It is increasingly recognized that even prolonged low-dose therapy may cause some of these side effects (9).
Methotrexate (MTX) is an immunosuppressive agent that has been used successfully in a wide variety of pediatric rheumatic diseases (10, 11). Experience gained from the use of MTX in childhood arthritis has shown that low-dose therapy is safe, with little reported long-term toxicity. In small, uncontrolled, retrospective studies (12–16), MTX was suggested to be beneficial as adjunctive therapy in patients with juvenile DM refractory to corticosteroids or in patients dependent on corticosteroids (12–16). Recently, Fisler et al conducted a review of the medical records of 35 children with juvenile DM, 23 of whom were started on a regimen of MTX after failing to respond within 6 weeks to corticosteroids. This cohort was considered to have had a good response to treatment and a decreased incidence of calcinosis (17). At followup, 5 patients (14%) had mild calcinosis; this rate is lower than the rate of ∼33% observed in other studies (18).
As a result of these studies, there has been interest in starting MTX earlier in patients with disease refractory to corticosteroid treatment, similar to the early use of MTX or azathioprine in adult DM. However, corticosteroids remain the initial treatment for the majority of patients with juvenile DM. For example, Wulffraat et al surveyed 50 pediatric rheumatology centers in 30 countries representing the Paediatric Rheumatology International Trials Organization. They found that in all centers corticosteroids were used initially, and that only 17 centers considered using MTX adjunctively as a first-line agent (19). There are no controlled studies of MTX as a first-line agent, with or without concomitant steroid therapy, in the treatment of patients with juvenile DM.
Our research question was as follows: does treatment of juvenile DM with MTX and an aggressively tapered course of corticosteroids result in a decreased cumulative dose of corticosteroids, while not compromising treatment efficacy, when compared with the standard regimen in which corticosteroids are tapered more slowly? We hypothesized that our approach of using MTX along with an aggressively tapered course of corticosteroids is as effective as the traditional regimen, results in a lower cumulative dose of corticosteroids and fewer corticosteroid-related adverse effects, and is safe in terms of MTX side effects.
We present the results of our cohort study, in which patients treated with MTX in combination with a course of aggressively tapered corticosteroids were compared with historical controls from our institution who were treated according to the traditional approach of a lengthy course of corticosteroids.
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- PATIENTS AND METHODS
Low-dose MTX along with a course of rapidly tapered prednisone, when used as initial therapy for juvenile DM, resulted in good control of disease activity as well as a reduction in the cumulative dose of corticosteroids. This therapeutic approach was associated with fewer corticosteroid side effects, and significant side effects of MTX were not observed.
MTX appears to be safe for use as first-line therapy in juvenile DM. The major concerns regarding MTX include hepatotoxicity, an increased risk of infection, and GI upset (28). In our study, there was no apparent increase in hepatotoxicity or severe GI upset in the group receiving MTX. Overall, the levels of transaminase elevation did not differ between the 2 groups. One patient receiving MTX discontinued the medication because of persistently elevated transaminase levels, but a liver biopsy revealed no significant pathology. Liver biopsies were not warranted in any of the other patients in the study.
In our study, patients were followed up for a relatively short period of time. In the study group, we were able to successfully wean patients off prednisone at a much quicker rate than had been attempted in the control group, and therefore the cumulative prednisone dose and the median time receiving prednisone were significantly less in the study group. Correspondingly, there was less of an increase in BMI, greater height velocity during the early period, and a decreased rate of cataract development in the study group patients over the first 2 years. However, it is unclear whether the benefits of this new approach will continue. Also, some patients with juvenile DM have been reported to experience slowly progressive late morbidity and disability (29). It is possible that our MTX-treated patients will have a different long-term experience than the traditionally treated group. Longer followup is required to identify possible long-term benefits of reduced prednisone exposure, such as changes in bone density and fracture rates.
It is certainly possible that not all of our patients need additional early treatment with MTX; there may be subgroups of patients who would tolerate rapid withdrawal of corticosteroids without any additional treatment. Indeed, a subgroup of 3 of 7 patients from British Columbia who had mild disease were treated with intravenous methylprednisolone infusions on a regular schedule and never needed daily corticosteroids (30). In fact, it is possible that MTX did not add any additional benefit; we may have been able to treat control patients with more rapid corticosteroid tapering without compromising their care. However, it is traditionally believed that shorter courses of corticosteroids result in inadequate disease control and the development of complications (6, 29). Our rationale for using MTX to treat all new patients with juvenile DM was 2-fold: we currently do not have accurate methods for determining which patients with juvenile DM will have a milder disease course, and MTX appears to be very safe when used in low doses to treat rheumatic diseases.
It must be noted that our study patients were treated more often with IVIG than were control patients, although the difference was not statistically significant. At our center we often use IVIG to treat steroid-resistant disease (31). The aforementioned discrepancy is most likely attributable to undertreatment in the control group due to a worldwide shortage of IVIG products during that time period. However, it is certainly possible that IVIG was used more often in the study patients in response to features of disease activity (e.g., continued rash) that resulted from a decrease in the amount of corticosteroids used.
Our results must be considered in light of potential limitations due to our study design. Several of the control patients were eventually treated with MTX. Such treatment represents a form of contamination: by including these children we may have underestimated the potential steroid-sparing effect of MTX. Moreover, we used historical controls, and this method may have introduced bias. There may have been temporal changes in the types of patients presenting to our clinic or changes in other aspects of treatment rather than the MTX protocol. These factors cannot be accounted for unless contemporaneous controls are used. However, our treatments were based on standardized protocols, and data were carefully collected onto standardized forms at the time patients were seen. Also, the same staff at a single center followed up the 2 groups of patients. We believe that we have minimized the potential bias associated with comparisons using historical controls.
Our study should be considered a preliminary step in the assessment of the role of MTX in the initial management of juvenile DM. The results of our study suggest that patients treated with MTX and a course of aggressively tapered prednisone have less exposure to corticosteroids and therefore may experience less associated toxicity. In conclusion, MTX in conjunction with an aggressively tapered course of prednisone may be as effective as traditional long-term corticosteroid therapy while decreasing the cumulative dose of corticosteroids in these patients.