Therapy of polymyositis and dermatomyositis

Abstract

Because polymyositis and dermatomyositis (PM/DM) are uncommon conditions, few randomized placebo controlled studies have been performed in these patients. The first line of therapy consists in high-dose oral prednisone, prescribed at 1 mg/kg/day, then progressively tapered based on patients' clinical response. In patients who do not improve with corticosteroids alone, methotrexate is added, the therapeutic effect of which being observed within 8 weeks. If PM/DM patients are refractory to corticosteroids and methotrexate, intravenous immunoglobulins can be added. In patients who fail to respond to this therapeutic strategy, it is crucial to make sure that the correct diagnosis has been made and we strongly recommend to perform a new muscle biopsy in order to exclude other myopathies. If the diagnosis of PM/DM is confirmed, a number of therapeutic agents may be proposed, including mycophenolate mofetil and rituximab. Importantly, TNF-α antagonists should not be considered in PM/DM patients, as these agents have been shown to favor exacerbation of interstitial lung disease and myositis and increase the risk of severe pyogenic and opportunistic infections in PM/DM patients.

Introduction

Polymyositis (PM) and dermatomyositis (DM) are systemic inflammatory disorders affecting the skeletal muscles, the skin and other organs [1], [2], [3], [4], [5], [6], [7], [8]. The diagnosis for PM/DM is based on Bohan and Peter criteria [9], [10]: i) symmetric proximal muscle weakness; ii) increased serum muscle enzymes; iii) myopathic changes upon electromyography; iv) typical histological findings on muscle biopsy; and v) typical dermatologic manifestations in DM such as heliotrope rash or Gottron's papules.

The causes of PM and DM are still unclear, although an autoimmune process is markedly implicated. In PM, CD8⁺ cytotoxic T-cells form immunological synapses with muscle fibers they invade, resulting in perforin-induced myocyte necrosis [11]. In DM, early activation of the complement cascade leads to the formation and deposition of the membranolytic attack complex on endomysial capillaries, resulting in muscle ischemia [12]. Although this key pathophysiologic event in PM/DM has strengthened the prospects for targeted immunotherapy in these conditions, the lack of identification of target autoantigens represents a major hurdle for the definition of specific immunotherapy in PM/DM. Nevertheless, to date, non-specific immunotherapeutic drugs have markedly improved the outcome of PM/DM patients (Table 1) and treatment does not selectively target pathogenic autoreactive T-cells in PM or complement-mediated processes in DM.

Indeed, before the use of corticosteroids, the prognosis of PM/DM was extremely poor, with a mortality rate as high as 50 to 61% [13]. To date, PM and DM are still considered to be associated with increased morbidity and mortality rates, primarily related to life-threatening muscle weakness and visceral involvement [2], [3], [4], [5], [6]. Because PM/DM are uncommon conditions with a prevalence of 11 per 100,000 subjects, it is difficult to study these orphan diseases in a randomized controlled fashion. Thus, until now, very few randomized controlled trials have been conducted to assess the optimal therapy in patients with PM/DM (Table 2), and those that have been completed included limited numbers of patients [14].