Inflammatory myopathies

4 Inflammatory myopathies C H E S T E R V. O D D I S T H O M A S A. M E D S G E R JR

Polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) are chronic, acquired inflammatory disorders of skeletal muscle that have been recently grouped under the rubric of idiopathic inflammatory myopathies (IIM) (Plotz et al, 1989). When a characteristic skin rash is present, the term dermatomyositis is used. Polymyositis and dermatomyositis may occur alone or in association with a wide variety of other rheumatic diseases (most notably systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus and Sj6gren's syndrome). P M - D M may also be seen in association with malignancy. In children, the most common presenting disease is dermatomyositis. The newest addition to the inflammatory myopathies is inclusion body myositis, an entity with characteristics that serve to both distinguish it, as well as group it, with the other myositis subsets. Although generally considered closely related, the disorders comprising PM-DM are quite heterogeneous in their clinical and laboratory manifestations, suggesting multiple aetiologies and pathogenetic mechanisms of disease expression. There are, however, certain unifying immunologic features of the distinctive myositis syndromes such as lymphocytic infiltrates of affected muscle, characteristic serum autoantibodies, and responsiveness to corticosteroids and other immunosuppressive agents. In this chapter we will discuss the historical development of the classification of myositis and the criteria used to diagnose myositis. We will compare the sensitivity and specificity of individual diagnostic criteria in myositis versus other diffuse connective tissue diseases (e.g. systemic lupus erythematosus and systemic sclerosis). Finally, we will review the available outcome measures of disease activity and discuss the strengths and weaknesses of the current classification system for myositis diagnosis and the parameters for disease assessment. H I S T O R I C A L ASPECTS According to clinical description, the first published case of dermatomyositis was recorded in Paris, France in 1875 (Potain, 1875). The patient died within one month and was reported only because of his unusual Bailli~re' s Clinical Rheumatology497 Vol. 9, No. 3, August 1995 ISBN 0-7020-1954-2

Copyright 9 1995, by Bailli~re Tindall All rights of reproduction in any form reserved

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features. Between 1886 and 1891 several German clinicians published cases of PM-DM and the first American report appeared in 1888 (Jacoby, 1888). The term polymyositis was introduced by Wagner in Germany in 1886 (Wagner, 1886), and Unverricht in Estonia coined the term dermatomyositis in 1891 (Unverricht, 1891). Nearly two-thirds of the 19th century case descriptions included associated cutaneous findings but 'Gottron's papules' were described by Gottron, a German dermatologist, in 1930 (Gottron, 1930). The first report of unequivocal DM in association with malignancy also came from Germany (Kankeleit, 1916), but a causal association between these two disease processes was not suggested until 1935. A more recent development was the first pathologic description of inclusions in muscle by Chou in 1967 (Chou, 1967), followed by use of the term inclusion body myositis by Carpenter in Canada in 1978 (Carpenter et al, 1978). CLASSIFICATION CRITERIA FOR MYOSITIS Classification schemes

The primary purpose of a classification system is to identify clinically homogeneous patient subsets with the goal of facilitating natural history and therapeutic intervention studies and directing laboratory investigation of disease pathogenesis. Considerable disparity exists between the many proposed classifications. Some have placed PM and DM in separate categories, whereas others combine the two but separate childhood disease from all adult forms. Some authors place myositis occurring in association with another connective tissue disease in a separate category while others believe this is unnecessary. Walton and Adams suggested the first classification scheme in 1958 (Table 1) (Walton and Adams, 1958). This scheme suffers from combining PM, DM and other connective tissue diseases in groups II and HI so that they cannot be easily separated. DeVere and Bradley used the Walton and Adams system in their comprehensive survey of 118 patients (DeVere and Bradley, 1975). They utilized the clinical features of muscle weakness and pain along with laboratory findings of abnormal muscle biopsy, myopathic electromyogram and raised serum creatine kinase (CK) in order to classify Table 1. Walton and Adams classification of polymyositis-dermatomyositis. Group I: Group II: Group III: Group IV:

Pure polymyositis, acute with myoglobinuria, subacute, or chronic; in childhood, early, middle, or late life Polymyositis with muscle weakness the dominant feature but with evidence of an associated collagen-vascular disease; or dermatomyositis with severe muscle disability and with skin changes which are often minimal or transient Severe collagen-vascular disease with muscular weakness due to polymyositis of comparatively minor degree; or dermatomyositis with florid skin changes Polymyositis or derrnatomyositis in association with malignant disease.

Reproduced from Walton and Adams (1958, permission.

Polymyositis, Baltimore: Williams and Wilkins) with

INFLAMMATORY MYOPATHIES

499

their patients into one of the four groups. These added requirements address another problem of the Walton and Adams criteria, that the diagnosis of PM is so inadequately specified that other conditions causing muscle weakness could be misclassified as PM. A second classification was proposed in 1968 by the Research Group on Neuromuscular Disease of the World Federation of Neurology and amended in 1974 (Research Group on Neuromuscular Diseases, 1968; Garner-Medwin and Walton, 1974). One section deals with PM and DM (Table 2) and makes a distinction between involvement of one organ system (muscle in PM) and more than one organ system (skin and muscle in DM). This separation is not a particularly logical one. For example, the myositis of PM and the myositis of Sjrgren's syndrome may be indistinguishable on clinical, laboratory and histopathologic grounds, yet they would be classified differently. In an attempt to overcome the difficulties of the two previous classification schemes, Bohan and Peter proposed a more simplified approach to PM-DM (Table 3) (Bohan and Peter, 1975). They emphasized that their Table 2. Classification of inflammatory myopathy by the Research Group on Neuromuscular Diseases (1968).* Other inflammatory disorders of muscle (c0 Polymyositis (possibly an organ-specific autoimmune disease) 1. Acute polymyositis and myoglobinuria 2. Subacute polymyositis 3. Chronic polymyositis (including chronic myositis fibrosa) (13) Polymyositis or dermatomyositis (when occurring as one feature of what may prove to be a nonorgan-specific autoimmune disease) 1. Dermatomyositis 2. Polymyositis in disseminated lupus erythematosus 3. Polymyositis in rheumatic fever 4. Polymyositis in rheumatoid arthritis 5. Polymyositis in scleroderma and/or systemic sclerosis 6. Scleroderma (morphea) with myopathy 7. Ocular myositis (pseudotumour of the orbit) 8. Muscle infarction and/or polymyositis in polyarteritis nodosa 9. Polymyositis in Sjrgren's syndrome 10. Polymyositis in Werner's disease (y) Polymyositis or dermatomyositis occurring in malignant disease (8) Polymyositis with associated virus particles * From Research Group on Neuromuscular Disease, (1968, Journal of Neurological Sciences 6: 165) with permission.

Table 3. Bohan and Peter classification of polymyositis-dermatomyositis (Bohan and Peter, 1975). Group 1: Primary idiopathic polymyositis Group 2: Primary idiopathic dermatomyositis Group 3: Dermatomyositis (or polymyositis) associated with neoplasia Group 4: Childhood dermatomyositis (or polymyositis) associated with vasculitis Group 5: Polymyosifis or dermatomyositis associated with collagen-vascular disease (overlap group) Abbreviation: PM-DM = polymyositis-dermatomyositis.

500

C. V. ODDIS AND T. A. MEDSGER

classification into five subgroups was not based on convincing clinical evidence that distinctive features existed between the various groups, but rather that future differences would most likely emerge from careful data analysis of the proposed subgroups (Bohan et al, 1977). Although this system is simple and practical, it has important limitations. First, vasculitis is not limited to childhood DM or PM, as implied. Second, the group 5 designation of myositis in overlap with another connective tissue disease is too loosely defined. Is Raynaud's phenomenon or pulmonary interstitial fibrosis considered to be another connective tissue disease? Finally, recent developments such as the description of IBM and the discovery of myositis-specific serum autoantibodies cannot be easily incorporated into the Bohan and Peter system. Nevertheless, their separation of inflammatory myopathy patients into clinical subsets has provided a useful framework for describing prognosis and the effects of therapy. Relationship of autoantibodies to clinical classification During the last decade, there have been exciting observations on the heterogeneity of the clinical subsets of myositis. The identification of IBM and the discovery of myositis-specific serum autoantibodies and their clinical and human leukocyte antigen (HLA) associations are two major developments. These newly described findings are reviewed below since they affect the need for re-classification of the inflammatory myopathies. At least 80% of myositis patients have serum antibodies to recognizable nuclear and/or cytoplasmic antigens, and approximately half of these antibodies are found only in myositis patients (so called myositis-specific antibodies or MSA) (Love et al, 1991). Many of the MSA are directed against ribonucleoproteins involved in the process of translation and they inhibit the function of their target autoantigen. Autoantibodies which occur in patients with other rheumatic diseases may also be seen in myositis patients and are termed myositis-associated antibodies. Patients who have myositis-associated but not myositis-specific autoantibodies can thus be termed MSA negative. Anti-Jo-1 antibody is the most frequently identified MSA. It is detected in approximately 20% of myositis patients and is the most common of the group of antibodies termed the anti-aminoacyl-tRNA synthetases (Arnett et al, 1981). These autoantibodies are directed against the enzymes that catalyse the binding of an amino acid to its cognate transfer RNA in the process of protein biosynthesis. Anti-Jo-1 is directed against histidyl-tRNA synthetase. Interestingly, patients with anti-synthetase autoantibodies generally present with the acute onset of symptoms and often have interstitial lung disease (ILD), polyarthritis, Raynaud's syndrome, fever and a characteristic rash on their fingers termed 'mechanic's hands' (Plotz et al, 1989). Response to therapy is fair and patients often have relapses and a guarded prognosis with a five year survival of less than 70%. There is a strong immunogenetic association of the anti-synthetases with HLA-DR3 and DRw52.

INFLAMMATORY MYOPATHIES

501

Antibodies to signal recognition particle (SRP) identify a second subgroup of myositis patients with MSA (Targoff et al, 1990). SRP is a cytoplasmic particle that binds to the signal sequence of newly formed proteins, and is involved in translocation of the protein into the endoplasmic reticulum. Anti-SRP is found in 5% of myositis patients who have an acute, often fulminant onset of severe muscle weakness without rash. These patients do not have ILD, arthritis or Raynaud's syndrome but they have a greater than expected frequency of cardiac complications. They generally respond poorly to corticosteroids and other forms of therapy and have a poor prognosis with a five year survival of 25% (Miller, 1991). Anti-SRP antibody is associated with HLA-DR5 and DRw52. The third category of MSA includes anti-Mi-2, also found in only 5-10% of myositis patients and characterized by the severe rash of DM (Targoff and Reichlin, 1985). Patients with adult, childhood, overlap and even malignancy-related myositis have been reported with anti-Mi-2. These patients have no features in common with anti-synthetase or anti-SRP patients, and generally have a good response to therapy (except for the rash) and a favourable prognosis. They have an increased frequency of HLA-DR7 and also a DRw53 association. Anti-MAS, which appears to have an increased frequency in alcoholics with rhabdomyolysis (Love et al, 1991), is another autoantibody with a prognosis similar to that of anti-Mi2. Anti-MAS is also associated with DRw53. A fourth category is a clinical one which includes patients designated as having IBM. These individuals are generally older males with an insidious onset of muscle weakness that affects both proximal and distal musculature. Falling episodes are common due to quadriceps atrophy. Fine motor movements that depend on distal muscle strength are compromised. These patients have a combination of neuropathic and myopathic features and characteristic eosinophilic inclusions on muscle biopsy. The mortality rate is low but IBM patients respond poorly to standard forms of therapy. Serologic and immunogenetic features of a new myositis classification scheme

Based on the autoantibody subsets defined above as well as the newly described clinical subset of IBM, Love et al compared the usefulness of a 'clinical' classification to a 'serological' grouping in 212 patients (Table 4) (Love et al, 1991). The classic clinical groups, which bear a close resemblance to the Bohan and Peter classification, differed little from one another regarding demographic characteristics, signs and symptoms, HLA associations and prognosis. Exceptions were that IBM patients had distinctive features, and overlap patients were heterogeneous in extramuscular findings and had milder, easier to treat skeletal muscle disease. In contrast, the serologic classification clearly defined more homogeneous groups of myositis patients. Signs and symptoms neatly segregated with the different MSA as described above, and prognosis, as defined by survival, also correlated with the particular MSA (Figure 1). The authors carried their

502

c.v.

ODDIS AND T. A. MEDSGER

Table 4. Proposed clinical and serologic classification based on 212 patient NIH cohort.* PM DM CTM CAM IBM

CLINICAL GROUPS Primary polymyositis Primary dermatomyositis Myositis with another connective tissue disease Cancer diagnosed within 1 year of diagnosis of myositiS Inclusion body myositis SEROLOGICAL GROUPS

Autoantibody

Antigen

Anti-synthetase Anti-SRP Anti-Mi-2 Anti-MAS MSA negative

1 of 5 known aminoacyl-tRNA synthetases Proteins of signal recognition particle Primarily directed against a 220 kDa nuclear protein of unknown function Sera precipitating a common 4S RNA of unknown function No known myositis-specific autoantibodies

Abbreviations: NIH = National Institutes of Health, MSA= myositis specific antibodies, SRP = signal recognition particle. * Adapted from Love et al (1991) with permission.

classification one step further utilizing two major immunogenetic subsets, those with DRw52-associated antibodies directed against translational components (more severe myositis and a worse prognosis) and those with DRw53-associated antibodies (less severe myositis and a better prognosis). Thus, using MSA status and HLA associations, they proposed a classification of inflammatory myopathy outlined in Figure 2. This very promising advance in classification also has important limitations. First, juvenile dermatomyositis was inadequately studied in this cohort and is essentially excluded in the classification process. Second, the patient database which generated the classification represents a highly selected group of patients seen at the National Institutes of Health, and may not be representative of myositis patients seen in the community or even at other university referral centres. Finally, most myositis patients do not have MSA, and other MSA have been described which are not included in the classification scheme recommended above. The result is a large, perhaps too heterogeneous group of myositis patients who are termed 'MSA negative.

Histopathologic features in the classification of myositis Dalakas has proposed yet another classification scheme, contending that PM, DM and IBM represent three different diseases based on their characteristic different clinical, immunopathologic and morphologic features, regardless of whether they occur separately or in overlap with other systemic diseases (Dalakas, 1991, 1992). Although the clinical heterogeneity of these subgroups is well established, it is Dalakas' view that the immunopathologic features of the muscle biopsy serve to distinguish the subsets of myositis from each other. In DM, the endomysial infiltrates have a greater number of B cells, a higher ratio of CD4 (helper) to CD8 (suppressor/cytotoxic) T cells, and a close proximity of the CD4+ cells to B cells and macrophages. This suggests an immune mediated

INFLAMMATORY MYOPATHIES

503

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S u r v i v a l t i m e (years) Figure 1. Kaplan-Meier analysis of survival in the clinical (top) and serologic (bottom) groups of patients with myositis from the NIH (see also Table 4). Patients with 1BM had significantIy prolonged survival from the time of diagnosis (P__<_0.05) when compared with PM and DM patients. In the serologic groups there was an increased mortality in the SRP group compared with those without SRF autoantibodies and in the synthetase-positive patients compared with patients with either Mi-2 or those without MSA. Abbreviations: IBM = inclusion body myositis, CTM = myositis with another connective tissue disease, PM = polymyositis, DM = dermatomyositis, CAM = cancer diagnosed within one year of diagnosis of myositis, SRP = signal recognition particle, MSA = myositis-specific antibodies. Synthetase=autoantibodies to 1 of the 5 known aminoacyl-tRNA synthetases, MSA- = no known myositis-specific autoantibodies. From Love et al (1991).

504

C. V. ODDIS AND T. A. MEDSGER

IDRw52 associatedI

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Figure 2. Second NIH classification of the idiopathic inflammatory myopathies utilizing the myositisspecific autoantibody status and irtmlunogenetics. HLA = human leukocyte antigens, MSA = myositis specific antibodies. From Love et al (1991).

process that is primarily humoral. The attack is directed against the intramuscular microvasculature and there is deposition of the C5b-9 membranolytic attack complex (MAC) implying activation of the complement pathway (Kissel et al, 1986). The end result is a reduction in the number of capillaries within muscle fibres as well as residual perifasicular atrophy reflecting adjacent hypoperfusion. In contrast, PM and IBM do not demonstrate the microangiopathy of DM, but instead are characterized by an antigen-directed cytotoxic T cell-mediated attack on muscle fibres expressing class I major histocompatibility complex antigen (MHC-I). CD8+ cells and macrophages have been shown to surround healthy, non-necrotic fibres and to attack and eventually destroy them (Engel and Arahata, 1986). Thus, although the target antigen is unknown, the immunopathologic mechanism in PM and IBM is mediated by cytotoxic T ceils restricted to MHC-1 antigen (Karpati et al, 1988). Further evidence that the pathogenetic process in DM is inherently different from PM comes from a muscle biopsy study of 25 PM and DM patients where qualitative and morphometric capillary analysis was carded out using phase and electron microscopy. The microvasculature of muscle was considered abnormal when more than 30% of capillaries showed structural changes. Using this criterion of abnormal capillary structure, DM was detected with a sensitivity of 90% and a specificity of 100% compared with PM (Estruch et al, 1992). Dalakas, therefore, proposes the classification shown in Table 5 for inflammatory myopathies and associated conditions. Some peculiarities of this classification include the fact that DM and not PM is felt to overlap with other connective tissue diseases and that DM only overlaps with systemic sclerosis and mixed connective tissue disease (Dalakas, 1991). In addition, although Dalakas recognizes the importance of myositis specific autoantibodies, they are not incorporated into his classification scheme.

INFLAMMATORY MYOPATHIES

505

Table 5. Dalakas classification of inflammatory myopathy and associated conditions.* Inclusion body Associations

Dermatomyositis

Polymyositis

myositls

Age of onset

Adults and children

Adults > 18 years

Adults > 50 years

Associated with connective tissue

Yes, with scleroderma and mixed connective tissue disease

Yes

Yes, in up to 15% of cases

Yes, with scleroderma

No

No

diseases Overlaps with

connective tissue

and mixed connective

diseases

tissue diseases

Associated with systemic autoimmune diseases

Infrequently

Frequently

Infrequently

Associated with malignancies

Probably

No

No

Associated with viruses

Unproved

With HIV, HTLV-1: possibly with other viral or postviral conditions

Unproved

Associated with parasites and bacteria

No

Yes

No

Associated with druginduced myotoxicity

Yes

Yes

No

Familial association

No

No

Yes, in some cases

* Adapted from Dalakas (1992) with permission.

In summary, there are many proposed classifications for the inflammatory myopathies. More recent schemes have incorporated well-defined clinical descriptive features as well as newly identified autoantibody associations and immunopathological mechanisms of disease pathogenesis. The challenge for the future will be to select classification criteria which allow investigators to answer most effectively questions on the aetiology, pathogenesis, epidemiology, response to therapy and prognosis of patients with inflammatory myopathy. D I A G N O S T I C CRITERIA F O R MYOSITIS There are only three clearly reported criteria sets for the diagnosis of myositis. In the 1970 study by Medsger et al on the epidemiology of PM in Shelby County, Tennessee, criteria were proposed for making the diagnosis on retrospective medical record review (Table 6) (Medsger et al, 1970). Cases were classified as definite PM if they met criteria 1 and 2 or 1, 3 and 4. Probable cases met criteria 1 and 3 or 1 and 4 and possible cases met criteria 1 and 5. Ninety (72%) of 124 study patients were classified as definite, 22 (18%) as probable and 12 (10%) as possible polymyositis. Cases were classified as 'possible' mainly because one or more of the test

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C. V. ODDIS AND T. A. MEDSGER

criteria had not been performed. The number of cases meeting each of the criteria was not stated, thus precluding an analysis of individual criterion sensitivity. These criteria lack definition of terms, making them difficult for other investigators to apply. The precise meanings of 'typical', 'consistent with' and 'characteristic' are uncertain, leaving too much latitude in interpretation for the chart reviewer. A distinguishing feature of this criteria set is the inclusion of a treatment response as an aid to diagnosis. Using corticosteroid responsiveness as a diagnostic criterion is probably unwise as some non-inflammatory myopathies such as lipid storage myopathy and muscular dystrophies may also respond to prednisone (Engel and Siekert, 1972). In addition, some patients with myositis may be refractory to corticosteroids and though it does reflect muscle damage, urine creatine excretion is rarely measured today. Table 6. Criteria for the diagnosis of PM-DM based on retrospective record review. 1.

characteristic history of muscle involvement with physical examination documenting muscle weakness

2,

muscle biopsy typical of polymyositis

3.

electromyogram (EMG) consistent with myositis

4.

any one or group of abnormal serum enzymes (CK, aspartate aminotransferase (AST or SGOT) or aldolase) compatible with polymyositis or elevated urine creatine excretion

5.

significant subjective and objective improvement in muscle weakness following administration of corticosteroids

Abbreviations: PM-DM = polymyositis--dermatomyositis, CK = creatine kinase. Reproduced from Medsger et al (1970, American Journal of Medicine 48: 715-723) with permission.

DeVere and Bradley used the criteria noted in Table 7 to evaluate their 118 patients (DeVere and Bradley, 1975). Muscle pain, weakness and a characteristic electromyogram (EMG) and/or muscle biopsy was present in 65 patients (55%). Nineteen additional patients (16%) had weakness without pain, with both a characteristic EMG and muscle biopsy; 20 (17%) had weakness and an abnormal biopsy. Thus 104 or 88% of the patients were accepted as having 'clearly documented polymyositis', which most accurately translates to definite disease in other systems. An additional 8 (7%) had weakness and an abnormal EMG and the remaining 6 patients (5%) had muscle pain and weakness and elevated CK levels in conjunction with another connective tissue disease. The terms are sufficiently defined to Table 7. DeVere and Bradley criteria for the diagnosis of polymyositis. 1.

muscle weakness - usually proximal and symmetrical

2.

muscle pain and tenderness

3.

muscle biopsy with perivascular inflammatory cell infiltration with or without muscle fibre degeneration

4.

electromyography with spontaneous activity and myopathic changes

5.

raised serum creatine kinase (CK) activity

Reproduced from DeVere and Bradley (1975).

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507

be used by other researchers. These criteria were unique in including muscle pain, but the sensitivity of this particular criterion was not stated. In fact, none of these individual criteria had their sensitivity reported, and no effort was made to test their specificity against non-inflammatory myopathies with which they could be confused. Bohan and Peter also introduced criteria for the diagnosis of PM and DM (Bohan and Peter, 1975). These criteria (Table 8) were proposed primarily for purposes of clinical research and the authors specifically state that the diagnosis of PM or DM is not excluded by the failure to meet these criteria. Definite disease requires 3 or 4 criteria (plus the rash) for DM and 4 criteria (without rash) for PM; probable disease must include 2 criteria (plus rash) for DM and 3 criteria (without rash) for PM; and possible disease requires 1 criteria (plus rash) for DM and 2 criteria (without rash) for PM. Some listed exclusions are central or peripheral neurologic disease, congenital muscular dystrophies, granulomatous myositis, infectious myopathy, metabolic or endocrine myopathies and myasthenia gravis. Table 8. Bohan and Peter criteria for the diagnosis of polymyositis and dermatomyositis. 1.

symmetrical weakness of the limb-girdle muscles and anterior neck flexors, progressing over weeks to months, with or without dysphagia or respiratory muscle involvement

2.

muscle-biopsy evidence of necrosis of myofibres, phagocytosis, regeneration with basophils, large vesicular sarcolemmal nuclei and prominent nucleoli, atrophy in a perifascicular distribution, variation in fibre size, and an inflammatory exudate, often perivascular

3.

elevation in serum of skeletal muscle enzymes, particularly the creatine kinase (CK) and often aldolase, aspartate aminotransferase (AST or SGOT), alanine aminotransferase (ALT or SGPT) and lactate dehydrogenase (LDH)

4.

electromyographic triad of short, small, polyphasic motor units, fibrillation, positive sharp waves and insertional irritability, and bizarre, high frequency repetitive discharges

5.

any one of the characteristic dermatologic features of the rash of dermatomyositis

Sensitivity and specificity of Bohan and Peter criteria The Bohan and Peter criteria have been the gold standard in subsequent studies of large myositis cohorts. The sensitivity of these criteria in several larger series of patients is summarized in Table 9 (Hochberg, t988). The combined sensitivity for definite and probable disease ranges from 74% to 100% in these 885 patients, with a mean of 91%. Most of the groups reported are referral in type, but one group of patients in which definite and probable PM-DM accounted for 85% represented a combination of both referral and primary care patients (Hoffman et al, 1983). We have assessed the performance of Bohan and Peter' s criteria in patients with systemic sclerosis, systemic lupus erythematosus, non-myositis overlap syndromes and inflammatory myopathy. As shown in Table 10, the sensitivity for definite myositis (PM or DM) in our inflammatory myopathy cohort was 56% while the combined sensitivity for definite and probable disease was 83%. (This relatively low sensitivity was due in part to many patients not receiving diagnostic tests such as an EMG or muscle biopsy.) In contrast, when Bohan and Peter's criteria were applied to the other control

508

C. V. ODDIS AND T. A. MEDSGER Table 9. Sensitivity of Bohan and Peter criteria for the diagnosis of PM-DM.

Patient source

Bohan and Peter classification (number of patients) Definite Probable (percent) (percent)

Bohan et al Henriksson and Sandstedt Hoffman et al Benbassat et al Tymms and Webb Hochberg et al Oddis et al

1977 1982

153 107

referral (university) hospital records

140 (92) 87 (81)

1983 1985 1985 1986 1990

27 92 105 76 177

Love et al Prasad et al Koh et al

1991 1992 1993

186" 73 75

referral and community 17 (63) hospital records 46 (50) hospital records 47 (45) referral (university) 56 (74) community hospital 86 (49) survey referral (NIH) 186 (100)t hospital records 56 (77) hospital records 49 (65)

Author(s)

Publication Number year of patients

TOTAL

1071

584/885 (66)

11 (7) 15 (14) 6 26 30 20 56

(22) (28) (29) (26) (32)

17 (23) 20 (27) 201/885 (23)

Adapted from Hochberg et al (1986). * Excludes inclusion body myositis. t All patients satisfied definite or probable criteria but breakdown not provided; excluded from total column and calculations.

Table 10. Sensitivity of Bohan and Peter criteria for the diagnosis of polymyositis-dermatomyositis (PM-DM) in the University of Pittsburgh Connective Tissue Disease Registry. Diagnosis

Definite myositis (%)

Probable or definite myositis (%)

PM-DM*

169/303 (56)

252/303 (83)t

Control Groups Systemic sclerosis Systemic lupus erythematosus Overlap (non-myositis) Combined controls

71/1628 (4) 18,846 (2) 509 (5) 94/2573 (4)

143/1628 (9) 26,846 (3) 6,99 (6) 175/2573 (7)~

* Includes patients with overlap if myositis also present. t Sensitivity = 83%. $ Specificity = 93%.

connective tissue diseases in the University of Pittsburgh database a specificity of 93% was found. Similar results were reported by Medsger when these criteria were applied to three cohorts of patients with systemic sclerosis, SLE and PM-DM from the Scleroderma Criteria Cooperative Study (Subcommittee for Scleroderma Criteria, 1980). As one can see in Table 11, the sensitivity of Bohan and Peter's criteria for the diagnosis of definite or probable disease was 93% in the myositis cohort, while a specificity of 93% was found when the control groups of SLE and systemic sclerosis were compared and analysed (Medsger, 1984). Unfortunately, there are no data available on other control groups of neuromuscular disease patients which may be diagnostically confused with myositis patients and which Bohan and Peter handled simply by terming them exclusions. Despite their good performance in external validation studies, the Bohan

509

INFLAMMATORY MYOPATHIES Table 11. Bohan and Peter criteria for polymyositis and dermatomyositis in patients enrolled in the scleroderma criteria cooperative study.*

Diagnosis Polymyositis/dermatomyositis Control groups: Systemic lupus erythematosus Systemic sclerosis Combined controls

Definite polymyositis or dermatomyositis

Probable or definite polymyositis or dermatomyositis

88/120 (73%)

111/120 (93%)t

1/172 (1%) 2/264 (1%) 3/436 (1%)

11/172 (6%) 20/264 (8%) 31/436 (7%)$

* Adapted from Hochberg (1988). "~Sensitivity = 93%. :~ Specificity = 93%.

and Peter criteria have perpetuated the problem of imprecise definition of terms. How elevated must the CK be? How many polyphasic potentials in an EMG qualifies as myositis? How many of the listed abnormalities must be present on muscle biopsy? While such ambiguities may be an inevitable problem in the development of diagnostic criteria, they nevertheless serve to emphasize that reviewer judgement and experience are important in the ultimate classification of patients. For this reason, some studies to design diagnostic or classification criteria have chosen a 'panel of experts' to review all submitted data collection forms to assure some minimal level of certainty concerning the final study diagnosis of all patients included in analysis (Subcommittee for Scleroderma Criteria, 1980). Another strategy is to request that submitting physicians confirm the diagnosis after an additional 1-2 years of follow-up. ASSESSMENT OF DISEASE ACTIVITY The laboratory evaluation of myositis includes various studies. With active inflammation, muscle enzymes leak from damaged myofibres resulting in elevated serum levels of the enzymes. CK is felt to be the most sensitive enzyme indicator of muscle injury, but aldolase, aspartate aminotransferase (AST or SGOT), alanine aminotransferase (ALT or SGPT) and lactate dehydrogenase (LDH) may also be elevated due to active myosifis. Myoglobin is released from injured muscle and is a more sensitive indicator of damage than serum CK, but its measurement is tedious and expensive (Lovece and Kagen, 1993). New markers of disease activity that are specific for only myocardium (troponin) or skeletal muscle (carbonic anhydrase 11I) are being evaluated (Wu and Perryman, 1992). The magnitude of CK elevation is not an absolute indicator of disease activity or eventual patient outcome, and there are many reports of normal CK levels at a time of biopsy-proven active myositis (Fudman and Schnitzer, 1986). Similarly, in a study of the quantitative assessment of quadriceps and hamstring muscle strength, some of the 14 patients with inflammatory myopathy studied showed a poor correlation between CK elevation and strength (Kroll et al, 1986).

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Several investigators have examined the levels of cytokines as an indication of inflammation in different rheumatic diseases including myositis. In two studies of 33 patients with PM-DM, soluble serum interleukin-2 (IL-2) receptors were measured as an indicator of activated T cells (Woff and Baethge, 1990; Tokano et al, 1992). Both observed elevated levels and one included a control population of normal subjects (Tokano et al, 1992). High dose prednisone led to a decline in soluble IL-2 receptor levels and there was a significant relationship between these levels and CK levels during treatment (Wolfe and Baethge, 1990). The serum levels of other cytokines and soluble IL-2 receptors were normal in patients with inactive or chronic disease. These studies suggest that activated lymphocytes may be detected in the peripheral blood of patients with myositis. Electromyography (EMG) is a sensitive but non-specific tool in the evaluation of inflammatory myopathy. It is useful initially in making the diagnosis of myositis and in selecting an appropriate site for muscle biopsy. EMG may be helpful in assessing disease activity in selected individuals when CK levels are normal or other parameters of disease activity are unavailable or judged not useful. In a correlation study on the degree of muscle weakness in 36 DM and 69 PM patients, a significant correlation was noted between muscle weakness and EMG results in PM but not DM patients (Tymms et al, 1990). Conversely, muscle weakness correlated with the serum CK and AST levels only in the dermatomyositis patients. A conceru is that repeated EMG studies are expensive and often painful. Muscle biopsy is generally recommended in cases of suspected myositis to confirm the diagnosis. Its sensitivity is limited due to sampling error; 20-30% of biopsies in typical myositis are normal. There are few studies on assessing disease activity based on biopsy abnormalities, and the procedure is obviously too invasive to be practically helpful in the longitudinal management of the individual patient. Magnetic resonance imaging (MRI) is a non-invasive tool recently reported in the diagnosis and management of patients with myositis. The recognition of muscle pathology is enhanced with newer MRI techniques that suppress the signal from fat and accentuate the resolution of inflammatory changes within muscle (Hernandez et al, 1992). The fat-suppressed (STIR) image signal intensity has been shown to correlate with both clinical activity of disease and inflammatory changes on muscle biopsy in adult and childhood myositis (Fraser et al, 1991; Hernandez et al, 1992, 1993). In 40 patients with myositis, the muscle STIR signal intensity was higher in patients with active versus inactive disease (Fraser et al, 1991). As might be expected, the MRI was more sensitive than biopsy in detecting active myositis in these patients. MRI changes have been reported in children with normal muscle enzymes, supporting the notion that MRI may be a reasonable alternative for confirmation of disease flare (particularly if the CK is normal), directing the site of selection for muscle biopsy and following patients non-invasively for disease activity over time (Heruandez et al, 1992). The current considerable expense and lack of experience in interpretation of MRI are limiting factors.

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P A R A M E T E R S OF O U T C O M E ASSESSMENT IN MYOSITIS The clinical evaluation of muscle strength and functional ability should be the most reliable guides to disease impact during the course of treatment. A quantitative assessment of muscle strength is clearly required to monitor the efficacy of therapy and follow the individual patient over time. Since the adverse effects of treatment are prevalent as well as serious, it is important to quantitate the beneficial effects of various therapies in order to determine their cost-benefit comparisons. A confounding issue is the fact that corticosteroids, the mainstay of therapy, are themselves capable of producing a proximal myopathy which is often difficult to distinguish from disease-related weakness. Assessment of muscle strength comes from the subjective report of the patient, the objective evaluation of the examiner and various measures of functional assessment in the form of monitored tasks or self-report questionnaires. The subjective report of the patient is important but unreliable, and must certainly be accompanied by an objective assessment of muscle strength. The most popular and most frequently reported method is the Medical Research Council War Memorandum scale (1943) (Table 12) (Aids to investigation of peripheral nerve injuries, 1943). This method is useful in distinguishing between normal and grossly abnormal muscle strength but is insensitive to slight weakness or the minor changes in muscle strength over time which are so characteristic of myositis. In addition, there is variability in testing between observers, and assessment may be flawed by poor patient co-operation. A simple method for the measurement of lower extremity strength using the time taken to rise to standing 10 times from a standard chair was reported in six consecutive myositis patients (Csuka and McCarty, 1985). Although simple, inexpensive and somewhat reproducible, this test also requires patient compliance and only measures lower extremity strength. The modified sphygmomanometer has been useful in detecting minor changes in muscle strength in rheumatoid arthritis patients (Helewa et al, 1981). True quantitative assessment of muscle strength is not conveniently available or easy to perform. Equipment is expensive and its use requires trained personnel. Several published studies illustrate the potential of such evaluation. Measurement of quadriceps and hamstring muscle strength were performed using isokinetic dynamometry and measuring isometric torque produced during maximum voluntary effort in 45 myositis patients (Kroll et al, 1988). In comparison with controls, myositis patients had Table 12. British Medical Research Council scale of muscle strength assessment. 0 1 2 3 4 5

No contraction Flicker or trace of contraction Active movement, with gravity eliminated Active movement against gravity Active movement against gravity and resistance Normal power

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preferential involvement of the quadriceps muscle compared with the hamstring group. In childhood myositis, 16 patients were followed longitudinally by quantitative muscle testing over a period of 10 years (Miller et al, 1988). The sensitivity of this method is illustrated by the fact that the time to achievement of normal muscle strength by quantitative measures was significantly delayed compared with the time to normal strength as measured by conventional manual methods. The inadequacies of currently available measures of the treatment response in myositis have been clearly elucidated (Mader and Keystone, 1993). Simple, inexpensive, more accurate and reproducible methods of quantitative muscle strength assessment are necessary. However, functional outcome in myositis patients is also dependent on other factors. Most patients with myositis have either persistent disease activity or multiple exacerbations and remissions necessitating chronic corticosteroid therapy and/or immunosuppressive drugs. In addition to the reversible myopathy, described above, the use of corticosteroids is associated with an impressive array of serious side effects that potentially contribute to longterm functional disability. For example, osteoporotic bone fractures and osteonecrosis involving large joints were shown to significantly increase disability in a large cohort of myositis patients completing a yearly functional assessment questionnaire (the Health Assessment Questionnaire) (Oddis et al, 1992). An appropriate disease-specific functional assessment tool has not, however, been developed for patients with inflammatory myopathy. SUMMARY

New information regarding myositis specific autoantibodies, histopathologic analysis of muscle biopsy specimens, and immunogenetic features of the different serologic subsets of disease has greatly increased our understanding of the pathogenesis of the inflammatory myopathies. The clinical descriptions of inclusion body myositis and 'amyopathic dermatomyositis' (Euwer and Sontheimer, 1993) are examples of our expanded descriptive capabilities in the evaluation of patients with myopathy. Finally, newer techniques such as cytokine analysis and magnetic resonance imaging may help in the ongoing assessment of disease activity in patients with myositis. The combination of these recently described clinical and laboratory parameters are enough to force a reconsideration of the previously described classification and diagnostic criteria in the inflammatory myopathies. REFERENCES Arnett FC, Hirsch TJ, Bias WB et al (1981) The Jo-1 antibody system in myosifis: relationship to clinical features and HLA. Journal of Rheumatology 8" 925-930. Benbassat J, Gefel D, Larholt K et al (1985) Prognostic factors in polymyositisfdermatomyositis. A computer-assisted analysis of ninety-two cases. Arthritis and Rheumatism 28: 249-255.

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