“Muscles … and bones”


  • David Isenberg

    Corresponding author
    1. University College of London, London, UK
    • Centre for Rheumatology, University College of London Division of Medicine, Room 331, 3rd Floor, Windeyer Building, 46 Cleveland Street, London W1T 4JF, UK
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When the Editor of Arthritis & Rheumatism invited me to contribute an editorial about the intriguing study by Christopher-Stine and colleagues (1) that appears in this issue, I was reading a newspaper article about the discovery of another link in the chain of human evolution. Analysis of DNA obtained from fragments of long-buried bones has identified Homo habilis. These “archaelogic” DNA analyses enable us to look in detail at human development without quite solving the mystery of our origin. An analogy with the discovery by Christopher-Stine et al of another abnormal antibody associated with idiopathic inflammatory myopathy (IIM) is irresistible. In this case, a further clue to the origin of a rare (but serious) linked set of diseases has been identified without enabling us to comprehend fully the origin of these disorders.

More than 25 years ago, the important link between autoantibodies and myositis was stressed by Reichlin and Arnett (2), who estimated, using the HEp-2 cell line, that 78% of 114 sera from patients with myositis were antinuclear antibody positive. This review appeared shortly after the seminal discovery by Mathews and Bernstein (3) of a myositis-specific autoantibody, now known as Jo-1, which binds histidyl transfer RNA (tRNA) synthetase. Subsequently, other autoantibodies binding to specific tRNA synthetases have been identified (Table 1). These too appear to be confined to the sera of patients with inflammatory muscle diseases.

Table 1. Syndromes associated with myositis-specific autoantibodies
  • *

    IIM = idiopathic inflammatory myopathy; DM = dermatomyositis.

  • Includes Jo-1 (anti-histidyl), PL-7 (anti-threonyl), PL-12 (anti-alanyl), OJ (anti-isoleucyl), EJ (anti-glycyl), HS (anti-asparingyl), ARS (anti-tyrosyl), and Zo (anti-phenylalanyl).

Antisynthetase syndromeAcute onset, interstitial lung disease, constitutional symptoms (fever), present in approximately one-third of patients with IIM, arthralgia/arthritis, Raynaud's phenomenon and mechanic's hands, moderate response to therapy but persistent disease
Anti–signal recognition particleVery acute onset/rapid progression, severe muscle weakness, absence of skin rash, present in <3% of patients with IIM, palpitations, necrotizing features on biopsy, poor response to therapy
Anti–Mi-2Acute onset, classic DM with V-sign and shawl-sign rashes in both adult and juvenile patients, cuticular overgrowth, present in 20% of patients with DM, good response to therapy
Anti–140/155 kdVariable speed of onset, present in both children and adults with DM (in adults, the antibody was linked to coincident cancer; in children, it was linked to ulceration, edema, and calcinosis), frequency in IIM not yet determined, generally more aggressive disease
Anti–100/200 kdAcute/subacute onset, very high creatine kinase level (>10,000 IU/liter), absence of skin rash, frequency in IIM not yet determined, necrotizing features on biopsy, complete/near complete response to immunosuppression in 60% of patients

Over the past 25 years, the advantage of detecting these and other antibodies, notably antibodies to the signal recognition particle (SRP) (4), has been evident. They clearly identify subgroups of patients, providing useful prognostic information for the clinician. Thus, antibodies to the tRNA synthetase enzymes are linked to patients who have a combination of inflammatory muscle disease and significant interstitial lung disease. In contrast, antibodies to the SRP (present in <3% of patients with IIM) are associated with an aggressive form of myositis that responds poorly to immunosuppressive therapy. These correlations are not absolute (5), but nevertheless, they alert the clinician to the likely disease pattern and the natural history of an individual case.

It is perhaps worth stressing that although inflammatory myositis clearly focuses on the skeletal muscles, constitutional features, pulmonary, cardiac, and gastrointestinal involvement, as well as dermatologic symptoms are all well-recognized concomitant features in many patients with IIM. This multisystem involvement is why the Myositis Intention-to-Treat Activity Index was developed: to assess the extent and severity of damage developing in different organs and systems (6). The value of a comprehensive clinical examination is emphasized in the study by Christopher-Stine et al (1), although they state only that the patients underwent “a comprehensive evaluation.”

The authors identified a group of 38 patients whose muscle biopy specimens demonstrated myofiber necrosis. Sera from 26 of these patients, assessed by conventional analysis, had failed to demonstrate any easily recognized autoantibody. Careful immunoprecipations were performed to analyze the binding of these sera with HeLa cells. Sixteen of these serum samples immunoprecipated a protein doublet with approximate sizes of 200 kd and 100 kd. Careful specificity analyses by the authors confirmed that this immunoprecipation was not observed with sera obtained from other patients known to have necrotizing myopathies associated with other known conditions, including those with anti-SRP, and serum from only 1 of 187 patients with myositis who did not have a predominant necrotic myopathy immunoprecipated this pair of proteins. A notably high creatine kinase level was common in these patients, with a mean value in excess of 10,000 IU/liter, and evidence of muscle edema was frequently seen on magnetic resonance imaging. The other notable serologic feature was the relative absence of moderately strong antinuclear antibody positivity (>1:160); just 1 patient was noted to have this. This feature obviously stands in contrast with the much higher value quoted by Reichlin and Arnett (2), as described above.

The other particularly intriguing feature of these 16 patients is that 10 of them had previously been treated with statins. For the vast majority of patients, statins are a safe and effective way of lowering the cholesterol level, but for a relatively small number of patients, myalgia is a recognized feature. Other drugs, including D-penicillamine, have also been described to induce a polymyositis such as inflammatory myopathy (7). This link between statins and a necrotizing myopathy has been noted previously (8) and prompts consideration of the immunopathogenesis of myositis in general and in this newly recognized subset of patients in particular.

In common with most autoimmune rheumatic diseases, IIM clearly has a genetic (9) and presumably a hormonal background, because the majority of patients are female, although the female-to-male ratio (2–3:1) is not as high as that in, for example, lupus or scleroderma. Pathogenic mechanisms seem certain to involve lymphocytes, cytokines, overexpression of particular antigens on muscle fiber, and abnormalities in muscle cell apoptosis and autoantibodies (for details, see refs.10 and11). Briefly, in patients with polymyositis, CD8+ T cells are more abundant in the endomysial areas. Non-necrotic myofibers may be surrounded, invaded, and destroyed by mononucleur cells, many of which are CD8+ lymphocytes. Subsequently, necrotic fibers are infiltrated predominantly by macrophages. Dead and dying endomysial cells are replaced by fat and fibrous tissue (which helps to explain why patients are weak).

Studies of the T cell receptors of the infiltrating lymphocytes are generally supportive of an antigen-directed T cell attack in patients with polymyositis. In contrast, a CD8+ T cell attack does not seem to be the problem in patients with dermatomyositis, in whom the muscle tissues show a much higher proportion of CD4+ T cells and B cells, particularly in the region immediately surrounding the blood vessels and muscle tissue. In contrast to polymyositis, endomysial infiltrates are rare. In dermatomyositis, damage to the small blood vessels appears to be mediated by complement, becauses the membrane attack complex of complement is found in and around the small blood vessels in the muscles of these patients compared with those with polymyositis.

There is usually no or very little expression of class I major histocompatibility complex (MHC) antigen on myofibers in normal individuals. In contrast, in many patients with IIM, muscle fibers strongly express class I MHC. This characteristic feature of immune-mediated myopathies was first reported by our group >30 years ago (12) and seems to have stood the test of time, because it is a very unusual finding in patients with other muscle diseases, such as dystrophies or primary neurologic problems. Regulation of class I antigens may be induced by interferon-γ, which was subsequently shown to be present on the sacrolemma/base membrane muscle fibers (13). Fifty percent of the available muscle biopsy specimens among the patients identified by Christopher-Stine et al had myofiber staining with class I MHC antigens.

Apart from interferon-γ, other cytokines, including tumor necrosis factor α, interleukin-1α (IL-1α), and IL-1β, have often been identified in muscle biopsy specimens from patients with IIM. They may well be important in the development, evolution, and perpetuation of an autoimmune attack, resulting in tissue damage such as that observed in these patients.

For many years, the role of autoantibodies in patients with myositis has been hotly debated (11). Are they simply a consequence of the autoimmune process or an integral part of it and integral to the inflammatory process? Casciola-Rosen et al (14) published an important study 5 years ago demonstrating augmented expression of a particular myositis autoantigenic target in the muscle of patients with myositis. This work is important, not least because it moves us a little closer to understanding why ubiquitous intracellular antigens might be involved in the autoimmune process. Thus, the expression of both Mi-2 (a helicase protein and a component of the nucleosome remodeling/histone deacetylase protein complex involved in chromatin remodeling) and Jo-1 were shown to be enhanced in the muscle of patients with myositis (15). The links between relevant autoantigen overexpression and autoantibody production have been reviewed recently (16).

Christopher-Stine and colleagues have described a novel subset of patients with an immune-mediated necrotizing myopathy characterized clinically by the subacute onset of proximal muscle weakness, very high creatine kinase levels, a variety of other clinical symptoms, including arthralgias, myalgias, and dysphagia, and prior statin use in two-thirds of the patients.

The connection between disease-specific autoantibodies to ubiquitous autoantigens that characterize IIM and its precise etiopathogenesis continues to challenge us. We need to understand more precisely how the mix of genetic, hormonal, and environmental factors actually combine and in what sequence to cause the clinical symptoms clearly described in this newly identified subset of patients. To obtain a more complete understanding of IIM, we need more muscle on the “bare bones” that have been uncovered so far.