COMMENTARY

The role of muscle enzymes in JDM

Juvenile dermatomyositis (JDM) is an autoimmune inflammatory disorder characterized by inflammation of the small vessels of the muscle, skin and other organs. The diagnosis is currently made using a combination of characteristic clinical features and laboratory investigations.[1-2] Elevated muscle enzyme levels have long been considered to play an integral part in the diagnosis and follow-up of children with JDM.

The muscle enzymes that are usually considered are creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and aldolase. In some institutions it is not possible to check serum aldolase levels. It is conventionally thought that these enzymes, normal constituents of the muscle fibers, “leak” out as a result of ischemic damage and inflammation in muscle, leading to higher than normal levels in the circulation. [3-5]

When considering a diagnostic test for JDM, it is important to know the test’s sensitivity (how often it is abnormal in those with JDM) and specificity (how often it is normal in those without JDM). It is well recognised that in JDM a proportion of children have no muscle enzyme elevation at the time of diagnosis. In 2 large case series, 17% and 10% of patients respectively had no muscle enzyme elevation at the time of diagnosis [1- 2]; the CK was normal in 31% in one recent series [6]. The sensitivity of having any muscle enzyme elevation is, therefore, about 0.8 to 0.9. The specificity is less clear; conditions that are likely to be part of the differential diagnosis of JDM (like viral myositis, or muscle dystrophies, etc.) are often associated with muscle enzyme elevation suggesting low specificity. Muscle enzymes should probably not play a major role in the diagnosis of JDM.

What role, then, do muscle enzyme elevations have in the follow-up of JDM?

It is not clear if the prognosis of patients without enzyme elevation at onset is any different from those with elevated enzymes at onset. For example, in a re-analysis of a study of 53 patients with JDM from Toronto, those with normal baseline muscle enzymes (about 10% of the group) had no difference in function or strength – up to 4 years following treatment – from those with abnormal baseline levels. Also, during follow-up the role of enzyme elevation is unclear. In a Brazilian series referenced above, muscle enzyme elevations were not helpful in measuring disease activity or in determining outcome. [4] This seems to reflect our clinical experience. For many patients with JDM, the muscle enzymes return to normal with the initiation of corticosteroid therapy, and then remain normal despite ongoing myositis as demonstrated by clinical signs and symptoms. In this clincial situation normal enzymes should probably not be too reassuring. Likewise, some of our patients have continuing high levels of CK without demonstrable myositis using other methods (e.g. strength testing, electromyogram, magnetic resonance imaging); presumably these patients have a focus of residual myositis somewhere but the clinical relevance is unclear.

A further difficulty is that enzyme elevation during the course of JDM can result from several processes apart from disease activity such as medication side effects (methotrexate induced elevation of ALT and AST reflecting an hepatic source), strenuous exercise, and rarely rhabdomyolysis, muscle trauma, or endocrine abnormalities [8-9].

In adult patients with myositis – where the CK is elevated in more than 90% of patients with polymyositis and DM – it is recognized that CK does correlate with myositis activity in some patients [3]. However, some adult studies suggest that it is not possible to make a correlation between CK and muscle strength or functional measures of disease activity [4]. Hence, CK cannot be used by itself to measure disease activity in spite of some evidence to suggest a general correlation of CK activity with disease activity [5]. In a recent review of this issue in adults, it was suggested that for some patients, increases in CK might antedate a clinical flare by about 6 weeks. The author also suggested that persistent elevation of CK is often a sign of ongoing inflammation, arguing for caution therefore in weaning treatment in such cases. Nonetheless, it was also recognized that in some patients the CK will be raised in the absence of clinical activity and that, conversely, corticosteroids may lower CK levels without adequate suppression of disease activity [5].

Our current understanding of the role of muscle enzymes in JDM is inadequate. More research needs to be done to answer questions such as: is the disease severity dependent on the type of enzyme elevated? What is the strength of association between elevated enzymes and active disease during the course of illness? Should we strive to normalize enzymes with aggressive therapy even when the disease is clinically quiescent? [10] The prognostic implications of the cohort of patients with no enzyme elevation at onset also needs to be more fully examined.

JDM is a rare disease – the incidence is 2-5 per million children per year [10-12]. With rare diseases such as JDM, an international collaborative effort will likely be required to fully answer these questions.

A. V. Ramanan, MD

B. M. Feldman MD, MSc, FRCPC

University of Toronto

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