Chapter 95 Inflammatory Myopathies
The inflammatory myopathies are a heterogeneous group of disorders characterized pathologically by inflammation in skeletal muscle, with resulting muscle fiber damage and subsequent clinical weakness. There are two major categories of inflammatory myopathy – idiopathic and infectious (Box 95-1). Although several types of muscular dystrophy may be associated with inflammation (e.g., facioscapulohumeral dystrophy and some of the limb-girdle dystrophies), these disorders traditionally are excluded from classification of inflammatory myopathy because they result from a fundamental genetic defect. The classic idiopathic inflammatory myopathies are usually considered autoimmune diseases, although a genetic predisposition may exist for many of these diseases based on inherited human leukocyte antigen haplotypes.
Box 95-1 The Inflammatory Myopathies
As a group, the inflammatory myopathies are the most common acquired myopathies of childhood. The infectious myositides are the most prevalent of these conditions worldwide, with acute viral myositis clearly the most common variety in North America and Europe. In contrast, the idiopathic varieties are relatively uncommon, with a combined incidence (including adult cases) of approximately 1 in 100,000 [Dalakas, 1991]. There are three major forms of idiopathic inflammatory myopathy – dermatomyositis, polymyositis, and inclusion body myositis – with dermatomyositis by far the most common form in childhood [Pachman, 1994]. Polymyositis is relatively uncommon in children and usually is seen as an overlap syndrome with other connective tissue disorders. Inclusion body myositis is exclusively a disease of adulthood and therefore is not discussed here.
Idiopathic Inflammatory Myopathies
Although clinicians frequently conceptualize the idiopathic inflammatory myopathies as a single entity (e.g., polymyositis is dermatomyositis without the rash), the disorders are clinically, histologically, and pathogenetically distinct. Banker and Victor [1966] first reported the unique vascular changes of juvenile dermatomyositis and highlighted the involvement of organs other than muscle and skin. Subsequent immunologic and pathologic observations confirmed distinct pathophysiologies for each of these disorders and recent observations have solidified this view. Although there have been occasional reports of siblings or parent/child cases of both dermatomyositis and polymyositis, most cases are sporadic.
Dermatomyositis
Clinical Features
Juvenile dermatomyositis can present at any age, including infancy, although most cases occur between ages 5 and 14 years. Females are affected more commonly than males. Onset of weakness is typically over weeks to a few months, although fatigue, muscle aches and stiffness, decreased activity, and fever can precede the onset of weakness by months. More acute, fulminate onset (over days) or an indolent, slowly progressive course (sometimes lasting a year) also has been described [Kissel et al., 1991; Pachman, 1994, 1995; Tymms and Webb, 1985]. Weakness typically affects the neck flexors and shoulder and pelvic girdle muscles first, so that the child may have difficulty getting up from the floor, riding a bicycle, running, climbing steps, or raising the arms above the head. Distal weakness is usually present, although not as severe as in proximal muscles. Complete sparing of distal strength should always lead the clinician to suspect another diagnosis, particularly one of the dystrophies. Dysphagia occurs in approximately one-third of patients, and rarely individuals also will have chewing difficulties, dysarthria, and speech delay because of oropharyngeal involvement.
The rash frequently precedes the muscle symptoms and often provides the most important clue to diagnosis [Bowyer et al., 1986; Sontheimer, 1999]. Skin changes typically involve the fingers and periorbital regions first, although any area may be involved. A purplish discoloration of the eyelids (heliotrope rash) with periorbital edema and extension on to the cheeks and forehead is typical (Figure 95-1). On the hands, the periungual regions become erythematous and scaly, with dilated capillary loops in the nailbeds (Figure 95-2). Papular, erythematous, scaly lesions over the knuckles (Gottron’s sign) are characteristic, with similar lesions occurring on the elbows, knees, and malleoli. A more macular, erythematous rash may appear on the face, neck, and anterior chest (V sign) or on the shoulders and upper back (shawl sign). Subcutaneous calcifications, which do not occur in adult cases, are present in 30–70 percent of childhood cases. The calcinosis tends to develop over pressure points (e.g., buttocks, knees, elbows) but can occur anywhere and develops more commonly when the diagnosis has been delayed or the treatment inadequate [Bowyer et al., 1983; Pachman, 1995]. The lesions typically appear as painful, hard nodules that erupt through the skin in severe cases. Occasional patients have the characteristic rash but never develop weakness, a condition sometimes referred to as dermatomyositis sine myositis or amyopathic dermatomyositis [Euwer and Sontheimer, 1993; Stonecipher, 1993].
Associated manifestations
Although involvement of organs other than muscle and skin has become less common with the advent of effective immunosuppressive therapies, some children will develop clinical manifestations, in addition to weakness and rash, on the basis of the underlying vasculopathy. About 50 percent will have electrocardiographic abnormalities, including conduction defects and dysrhythmias, and pericarditis, myocarditis, and congestive heart failure can occur [Askari, 1984; Haupt and Hutchins, 1982; Tymms and Webb, 1985]. Pulmonary function tests may demonstrate restrictive defects and reduced diffusion capacity, even in patients with no pulmonary symptoms [Pachman, 1994]. Approximately 10 percent of patients, particularly those with antibodies to histidyl transfer ribonucleic acid synthetase (Jo-1), develop frank interstitial lung disease or bronchiolitis obliterans and organizing pneumonia [Love et al., 1991]. Vasculopathic involvement of the gastrointestinal tract can result in malabsorption, mucosal ulceration, perforation, and hemorrhage. Dysphagia and delayed gastric emptying, caused by inflammatory involvement of the alimentary skeletal and smooth muscles, are more common.
Arthralgias are common, but true arthritis occurs mainly in children with an “overlap” connective tissue disorder (see below). Ophthalmic involvement on the basis of vascular changes in the retina and conjunctiva can occur [Pachman, 1995]. Renal compromise is rare and results from acute tubular necrosis in the setting of myoglobinuria after fulminant muscle necrosis [Rose et al., 1996]. In contrast to adult dermatomyositis patients, children have demonstrated no definitive increased incidence of malignancy [Sigugeirsson et al., 1992; Fardet et al., 2009].
Laboratory Features
The laboratory evaluation of patients with inflammatory myopathy should include muscle enzyme analysis, electrodiagnostic studies, and muscle biopsy. Muscle imaging studies can indicate areas of inflammation in affected muscles but are seldom useful in making a diagnosis [Hernandez et al., 1993].
Blood tests
Creatine kinase is the most reliable, sensitive, and specific marker for muscle destruction. The creatine kinase level is elevated in about 70 percent of patients sometime during the course of the disease, with levels up to 50 times normal [Amato et al., 1996; Dalakas, 1994a; Tymms and Webb, 1985]. However, it is important to note that the creatine kinase level can be normal throughout the course of the disease and does not correlate with weakness. Rarely, serum aldolase can be elevated when the serum creatine kinase is normal; serum myoglobin, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase can also be elevated but provide no additional information to the creatine kinase. Erythrocyte sedimentation rate is normal or mildly elevated and does not correlate with severity. Antinuclear antibodies occur in 25–50 percent of patients, most commonly in those with overlap syndromes.
Although myositis-specific antibodies associated with specific human leukocyte antigen haplotypes can be demonstrated in a minority of patients, they usually are identified in adults. There have been isolated reports of these antibodies in childhood dermatomyositis, although their role in the pathogenesis of the inflammatory myopathies, in both adult and childhood cases, is unclear [Love et al., 1991; Plotz et al., 1995; Gunawardena et al., 2009]. Although these antibodies provide some information about prognosis [Joffe et al., 1993; Miller, 1993], their value in diagnosing and managing patients is limited, and assaying for them routinely in children with suspected inflammatory myopathy is not indicated. The only exception is the Jo-1 antibody, which is commonly present in patients with interstitial lung disease. In these Jo-1-positive patients, the interstitial lung disease often is more refractory to treatment, and may require the initiation of therapy with prednisone and a second-line immunosuppressive agent (see “Treatment” later). The presence of interstitial lung disease is also a contraindication to the use of methotrexate, which itself can cause interstitial pulmonary fibrosis.
Muscle biopsy
The classic pathologic features associated with dermatomyositis include a microvasculopathy with capillary loss, perivascular and perimysial inflammation, perifascicular atrophy, and scattered areas of fibers with central areas of myofibriallar loss (Figure 95-3). The most characteristic of these changes is perifascicular atrophy, which is present in approximately 50 percent of cases and is relatively specific for dermatomyositis. The inflammatory infiltrates are predominantly perimysial and perivascular, and are composed primarily of macrophages, B cells, and CD4+ cells (Figure 95-4 and see below) [Arahata and Engel, 1984]. One of the earliest demonstrable histological abnormalities on light microscopy is deposition of C5b-9 complement membrane attack complex (MAC) on small blood vessels (as well as immunoglobulin M and other complement components, including C3 and C9) [Emslie-Smith and Engel, 1990; Kissel et al., 1986]. These immunohistochemical findings can be helpful in making a diagnosis, especially when other histologic findings are absent or equivocal. Electron microscopy typically reveals small intramuscular arterioles and capillaries with endothelial hyperplasia, microvacuoles, and cytoplasmic inclusions, but is seldom needed to make a diagnosis.
Pathogenesis
More recent evidence, however, has raised many questions about the interpretation of all of these observations and suggested other possible pathogenic mechanisms. The vascular MAC and immunoglobulin deposits, for example, could be due to either immune complex deposition, or complement activation by the classical antibody-mediated or alternative pathways [Greenberg and Amato, 2004], occurring as a secondary phenomenon after the microvasculature has been damaged by some other mechanism (e.g., interferon or other cytokine-related toxicity). The fact that some patients have developed dermatomyositis with hereditary complement deficiencies argues against a primary destruction of capillaries by complement and MAC.
Recent evidence has also suggested that factors other than ischemia may be responsible for the production of perifascicular atrophy [Greenberg and Amato, 2004]. In animal models of ischemic myopathy, for example, the pathological changes are located centrally within fascicles and the perifascicular regions are preferentially spared. In addition, perifascicular atrophy is not evident in ischemic muscle damaged by vasculitis. Gene expression studies on muscle biopsies from dermatomyositis patients do not reveal upregulation of genes normally associated with ischemia, suggesting that some other process may be operative in producing these changes [Greenberg et al., 2005].
Finally, although the inflammatory infiltrate in dermatomyositis is composed primarily of macrophages, B cells, and CD4+ cells in the perivascular and perimysial regions, the CD4+ cells are not T-helper cells, but rather predominantly plasmacytoid dendritic cells [Greenberg et al., 2005], which are the body’s primary producers of type 1 interferons. Gene expression and proteomic studies on muscle biopsies and in serum suggest that increased expression of type 1 interferons in patients with dermatomyositis might be directly toxic to small vessels and muscle fibers. Furthermore, capillaries and muscle fibers in dermatomyositis over-express type 1 interferon inducible proteins, particularly in the perifascicular regions, and these changes can be seen even before the development of perifascicular atrophy [Greenberg et al., 2005; Salajegheh et al., 2009]. These findings in muscle biopsies are also supported by observations suggesting that increased interferon-α and its inducible genes are seen in serum of patients with dermatomyositis and that the levels correlate with disease activity [Walsh et al., 2007; Niewold et al., 2009]. These observations, taken together, suggest that type 1 interferon over-expression, rather than a microvasculopathy, may be the pivotal event in producing the muscle damage in dermatomyositis, although what might trigger this over-expression is currently unknown.
Treatment
Although corticosteroids are generally regarded as the most effective therapy for dermatomyositis, there is disagreement surrounding the best route of administration, dosing regimen, duration of therapy, and parameters to monitor during therapy [Amato and Barohn, 2009]. There have been no controlled trials to examine these issues, although retrospective studies have demonstrated that prednisone reduces morbidity and improves strength and function [Adams and Plotz, 1995; Chwalinska-Sadowska and Madykowa, 1990; Dalakas, 1994a; Joffe et al., 1993].
Corticosteroids
Prednisone is the usual first line of treatment for dermatomyositis. Short courses of intravenous methylprednisolone (Solu-Medrol; 20–30 mg/kg/day or every other day for 3–5 days) may be the best way to initiate therapy in severely affected individuals, especially because this therapy may prevent calcinosis [Laxer et al., 1987]. A more traditional regimen involves oral therapy (1–2 mg/kg/day), given as a single morning dose. After 3–6 weeks of daily prednisone, the dosage usually can be switched directly to an alternate-day regimen at the same dose, although occasional patients will require persistent daily therapy. The high dose is maintained while strength is carefully monitored. Although the creatine kinase level can sometimes be useful in monitoring response, it should never be the primary determinant of therapeutic decision-making.
Patients should be evaluated at least monthly during this phase of treatment. When the child’s strength has returned to normal or improvement has reached a plateau (usually within 4–6 months), the prednisone can be tapered at a rate no faster than 5 mg every 2–4 weeks. If an exacerbation occurs during the tapering, the prednisone dose is increased back to its original level and again given daily. When strength has recovered, the prednisone taper can be resumed. Although occasional patients will require daily dosing, or even split daily doses to maintain adequate disease control, alternate-day dosing is preferred because it is associated with fewer side effects. Most patients (approximately 80 percent) improve with therapy, with approximately two-thirds having a complete response [Amato et al., 1996; Pachman, 1995].
As most patients require therapy for 1–2 years to achieve remission, limiting the side effects of prednisone is an important part of management [Boumpas et al., 1993]. Patients should be started on a low-sodium, low-carbohydrate, high-protein, low-calorie diet to limit weight gain and reduce the risk of hypertension. Calcium supplementation (1000–1500 mg/day) and vitamin D reduce the risk of osteoporosis, as does physical therapy with axial exercise, as tolerated by the patient’s weakness. Baseline determination of bone density through dual-energy x-ray absorptiometry scanning is indispensable in diagnosing and following osteoporosis in this population. Therapy with bisphosphonates should be considered in children who develop definite osteoporosis, or in those expected to be on very long-term therapy [Bianchi et al., 2000]. Exercise also reduces the risk of steroid myopathy [Escalante et al., 1993]. Blood pressure, serum glucose and potassium levels, and ocular status (for cataracts and glaucoma) should be assessed periodically. Hip pain in a child on prednisone must be investigated aggressively because avascular necrosis is an uncommon but devastating development in these individuals. Growth retardation and delayed puberty can occur with prolonged therapy.
