Inflammatory Myopathies

Abstract

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of disorders characterized by varied patterns of inflammation within striated muscle. The major disease categories among the IIM are der-matomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), myositis associated with connective tissue diseases, and myositis associated with malignancy. The skin, joints, lungs, heart, and gastrointestinal tract are also involved in different forms of these disorders. Muscle weakness that is proximal, symmetrical, and painless is a hallmark feature of the inflammatory myopathies. Patients with IBM are also prone to distal, asymmetric muscle involvement. Measurement of serum concentrations of muscle enzymes, skin and muscle biopsy, electromyography, and magnetic resonance imaging can assist in the diagnosis. Testing for serum autoantibodies is helpful both in diagnosis and in predicting the clinical phenotype and response to therapy. A minority of patients with DM and PM have myositis that is associated with an underlying malignancy. The risk is greatest for middle-aged to elderly patients with DM. Approximately 15% of DM patients have malignancy-associated disease. Most malignancies present within 1 year before or after the diagnosis of inflammatory myopathy.

18.1 Overview of the Inflammatory Myopathies

• The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of disorders characterized by varied patterns of inflammation within striated muscle.

• The major disease categories among the IIM are der-matomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), myositis associated with connective tissue diseases, and myositis associated with malignancy.

• The skin, joints, lungs, heart, and gastrointestinal tract are also involved in different forms of these disorders.

• Muscle weakness that is proximal, symmetrical, and painless is a hallmark feature of the inflammatory myopathies. Patients with IBM are also prone to distal, asymmetric muscle involvement.

• Measurement of serum concentrations of muscle enzymes, skin and muscle biopsy, electromyography, and magnetic resonance imaging can assist in the diagnosis.

• Testing for serum autoantibodies is helpful both in diagnosis and in predicting the clinical phenotype and response to therapy.

• A minority of patients with DM and PM have myositis that is associated with an underlying malignancy. The risk is greatest for middle-aged to elderly patients with DM. Approximately 15% of DM patients have malignancy-associated disease.

• Most malignancies present within 1 year before or after the diagnosis of inflammatory myopathy.

18.2 Dermatomyositis Versus Polymyositis

Myth: Dermatomyositis is polymyositis with a rash.

Reality: Although dermatomyositis (DM) and polymyositis (PM) share the term “myositis,” these disease entities should not be considered the same for many reasons. Pathologic differences suggest that DM is a humorally mediated vascul-opathy. In contrast, PM results from T cell-directed injury to the myocyte. Histologic examination of inflamed muscle in DM reveals more B cells, complement deposition, and CD4-positive T cells in perivascular regions. In contrast, PM is characterized by a predominantly CD8+ T cell infiltrate, with fewer B cells. Although the same autoantibodies can be found in DM and PM, some are associated with specific IIM subsets such as antisignal recognition particle (SRP) in PM and anti-Mi-2 in DM. Other differences include a substantially greater interferon-α/β-induced gene expression in DM when compared to PM.

Response to therapy also differentiates the myopathies. DM typically responds readily to glucocorticoids, but PM responds more slowly and often requires the addition of a second-line immunosuppressive agent.

18.3 Skin Disease

Pearl: Biopsy of any of the skin lesions in DM shows the same histology.

Comment: This is almost entirely correct! With the exception of the uncommon subcutaneous cystic lesions, biopsy of any skin lesion in DM will show focal epidermal atrophy, liquefaction, and degeneration of the basal cell layer and a perivascular or upper dermal mononuclear or lympho-cytic infiltrate. Immunofluorescence studies confirm the presence of an interface dermatitis, with positive staining for immunoglobulin or complement at the dermal—epidermal junction. Biopsies of Gottron's papules (Fig. 18.1a), heliotrope erythema (Fig. 18.1b), the shawl sign (Fig. 18.1c), and mechanic's hands (Fig. 18.1d) all reveal the same histo-pathological features. The dermatopathology of these lesions is depicted in Fig. 18.2.

Fig. 18.1

Cutaneous findings of dermatomyositis. Skin biopsy of any of these lesions shows the same histopathologic features (see Fig. 18.2) (a) Gottron's papules (b) Heliotrope erythema (c) Shawl sign (d) Mechanic's hands (Figures Courtesy of Dr. John Stone)

Fig. 18.2

Histopathology of the skin in dermatomyositis. A hematoxy-lin and eosin stain of a skin biopsy (× 100 magnification) reveals an atrophic epidermis, extensive dermal mucin deposition (pink-colored material), and only a mild dermal inflammatory infiltrate are seen (Figure courtesy of Dr. Mai Hoang, Massachusetts General Hospital)

Myth: Patients must have muscle disease to make a diagnosis of DM.

Reality: The original Bohan and Peter criteria required that patients have muscle disease in order to receive a diagnosis of DM (Bohan and Peter 1975). However, the pathogno-monic skin findings in patients with DM permit the diagnosis of “amyopathic” DM in the absence of muscle findings. The hallmark skin findings of DM include Gottron's papules and erythema over the extensor surfaces of joints, particularly the metacarpophalangeal and interphalangeal joints, the elbow, the malleoli, and the knee along with a heliotrope rash. Other characteristic but not pathognomonic findings include periungual erythema (Fig. 18.3) or capillary changes, dys-trophic cuticles, and a violaceous erythema found in a photodistribution.

Fig. 18.3

Periungual erythema in a patient with dermatomyositis (Figure courtesy of Dr. John Stone)

Patients with amyopathic DM have undiminished muscle strength, no muscle pain, and normal muscle enzymes (Gerami et al. 2006). Approximately one-third of DM patients who present to dermatologists have amyopathic DM. Another third has minimal muscle symptoms, with only subclinical evidence of myositis on laboratory and electrophysiologic evaluation and radiographic imaging (Quain et al. 2007).

Myth: Patients with amyopathic DM do not have the same risk of lung disease as those with DM who have muscle inflammation as well as skin disease.

Reality: Patients with amyopathic DM can have interstitial lung disease in the absence of muscle inflammation. In fact, one study reported that 25% of patients with amyopathic DM had interstitial lung disease (Quain et al. 2007). As a result, patients with amyopathic DM must be screened with pulmonary function tests (PFTs) that include measurement of diffusion capacity. Further evaluation of the lungs is required if this screen detects any abnormalities. Annual PFTs are appropriate assessments in patients with DM and PM.

Some patients with interstitial lung disease have erythema and/or roughness of the palmar surface and sides of the fin-gers and palm, otherwise known as “mechanic's hands.” This skin finding is associated with the antisynthetase syndrome (Quain et al. 2007).

Pearl: Patients with amyopathic DM should be screened for underlying malignancies.

Comment: Patients with DM have a higher risk of malignancy than do patients with PM (Buchbinder et al. 2001). Patients with amyopathic DM are also at an increased risk for cancer and the frequency of malignancy is likely similar in both classic DM and amyopathic DM (Gerami et al. 2006); thus, patients should be screened accordingly (Callen 2001). The cancers that are particularly increased in DM include lung, ovary, pancreas, stomach, colon, and rectum, as well as non-Hodgkin's lymphoma (Hill et al. 2001).

18.4 Muscle Enzymes

Myth: All patients with active myositis have an elevated cre-atine kinase concentration.

Reality: Serum creatine kinase (CK) activity levels do not correlate perfectly with muscle inflammation or weakness in myositis as muscle inflammation and weakness can be present without CK elevation. This is most often seen in DM, in both the adult and juvenile subsets (see below). The mechanism by which this occurs is not understood completely. Some patients may have an inhibitor of enzyme function that leads to an underestimation of the CK activity (Kagen and Aram 1987). The serum CK activity level may correlate better with the degree of muscle inflammation early in the course of the disease as opposed to later when muscle atrophy is more likely.

In patients with a normal CK, one or more of the other muscle enzymes (e.g., aldolase, lactic dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT)), or another muscle factor (e.g., myoglobin) may be elevated. However, as discussed below, serum enzyme concentrations should not exclusively guide treatment.

Even if the serum CK activity level remains within the range of normal, changes in activity levels within this range may be significant as elevations of the CK above the patient's baseline activity level may be important. Magnetic resonance imaging of the muscle is helpful in the assessment of disease activity when muscle weakness is present in the absence of muscle enzyme elevations.

Pearl: Muscle inflammation in the setting of a normal serum CK activity level is more likely in DM than in PM.

Comment: Active myositis with a normal CK is more common in DM than in PM, but must be distinguished from amyopathic DM (in which there is no clinical or laboratory evidence of muscle involvement). Even if cases of amyo-pathic DM are excluded, serum CK activity levels correlate less well with the severity of muscle involvement in DM than they do in PM.

PM is unlikely in the setting of a normal CK and is more difficult to diagnose than DM when the CK is not elevated. In fact, “definite” PM cannot be diagnosed according to the Bohan and Peter criteria without an elevation of serum muscle enzymes (Bohan and Peter 1975). Some reports indicate that normal CK activity levels in the setting of active myositis are likely to occur in patients with malignancy-associated myositis or inflammatory myopathy associated with a connective tissue disease, but reports of series of such patients are too small to permit definitive conclusions on this point.

Myth: The most important parameter in assessing disease activity in myositis patients is the concentration of muscle enzymes.

Reality: The main clinical manifestation of myositis is muscle weakness that translates into functional impairment and disability. Since the principal objective of treatment is the recovery and maintenance of normal strength through the suppression of muscle inflammation, the most important parameter to monitor is muscle strength, not serum enzyme concentrations.

This concept was incorporated into the consensus defini-tion of improvement for myositis established by a panel of experts (Rider et al. 2004). Muscle strength is most often assessed by manual muscle testing, but function can be ascertained by other approaches, including patient questionnaires. The serum CK and other muscle enzymes are indirect measures of muscle inflammation and can be misleading so the notion that myositis treatment should focus on CK normalization is a Myth.

However, despite the shortcomings of serum muscle enzyme measurements as a biomarker of disease activity, these determinations still play a role in the assessment of most myositis patients. Indeed, CK activity levels correlate well with other measures of disease activity in many patients and an increase in the serum CK in an otherwise stable patient serves as a potential warning of a disease exacerbation, assuming there is no intercurrent process such as muscle injury, hypothyroidism, or medication use to explain the abnormality.

Myth: Serum concentrations of ALT do not rise during periods of active inflammatory muscle disease because this enzyme is specific to the liver, not skeletal muscle.

Reality: Elevations in the serum ALT concentration can occur in muscle injury as well as with liver damage. Although there is more aspartate aminotransferase (AST) than ALT in muscle, serum ALT can rise when injury to skeletal muscle is significant.

The fact that ALT elevation can occur in muscle disease complicates the clinician's ability to detect medication-induced liver toxicity. The failure of the AST and ALT concentrations to fall in conjunction with the CK activity level as muscle strength improves may unmask the presence of drug-induced hepatotoxicity.

Myth: An elevated CK-MB activity level is a sign of cardiac damage in patients with myositis.

Reality: The CK-MB activity level and its proportional activity level when compared to that of the total CK can increase in myositis even in the absence of detectable cardiac muscle inflammation or injury. This is usually attributed to an increased proportion of CK-MB production by myoblasts in regenerating muscle. Cardiac muscle inflam-mation does occur in myositis and is sometimes clinically significant, but the more frequent occurrence of CK-MB elevation from noncardiac sources in patients with myositis makes it difficult to use CK-MB as a sign of cardiac damage.

Serum troponin-T levels have also been proposed as spe-cific markers of myocardial disease, but they too have been associated with myositis disease activity unrelated to cardiac involvement (unpublished observations and Erlacher et al. 2001). On the other hand, serum concentrations of cardiac troponin-I are usually normal in patients with PM or DM who do not have cardiac involvement (Erlacher et al. 2001). Consequently, elevations of cardiac troponin-I support an inflammatory process in the myocardium.

Myth: Aldolase is a muscle-specific enzyme.

Reality: Elevations of the serum CK are usually derived from muscle, particularly when the isotype is CK-MM. Skeletal muscle injury also results in the elevation of the serum aldolase activity, because skeletal muscle is rich in aldolase A. The CK activity level is generally a more sensitive and specific marker of muscle injury than is aldolase. The aldolase may be elevated in hemolytic states, with liver damage and in CNS disorders as aldolase B is found in the liver and other tissues. However, in some myositis patients, the serum CK may not correlate with disease activity and the serum aldolase is more useful in such unusual and rarely reported cases.

18.5 Myositis-Specific Autoantibodies

Myth: The “myositis-specific autoantibodies” are specific for myositis, as patients with one of these antibodies always have myositis.

Reality: The term “myositis-specific autoantibodies” (MSA) was first used to identify a group of autoantibodies that is associated primarily with myositis. MSAs have been distinguished from “myositis-associated autoantibodies” (MAAs), which may occur in myositis as well as other connective tissue diseases (CTD). The MSAs originally included the following:

• Antisynthetase antibodies (anti-Jo1 antibodies being the most common, but now also including at least seven other antibodies directed against aminoacyl-tRNA synthetases)

• Anti-SRP antibodies

• Anti-Mi-2 antibodies

These antibodies, when assessed by immunoprecipitation methods, generally have a specificity for myositis on the order of 90% or more, but previous studies have reported antisynthetase antibody-positive patients with ILD who do not have any clinical evidence of muscle inflammation (Friedman et al. 1996; Tillie-Leblond et al. 2008), or late onset myositis in the course of other CTDs (Tillie-Leblond et al. 2008; Schmidt et al. 2000). Anti-SRP autoantibodies may also not be as specific for myositis as originally reported (Kao et al. 2004), and although anti-Mi-2 autoantibodies are relatively specific for myositis by immunoprecipitation assays, antibodies to Mi-2 peptides may be seen in other conditions when measured by ELISA or immunoblotting (Hengstman et al. 2005).

The greatest utility of the MSAs occurs when the diagnosis is unclear, such as in the setting of possible myositis or another immunologic disorder where autoimmunity is presumed, such as in patients with ILD of unclear etiology (see below).

Pearl: Not all of the autoantibodies relevant to the IIMs have been identified.

Comment: The list grows longer every year. In addition to the antisynthetase, anti-SRP, and anti-Mi2 autoantibodies, several additional autoantibodies appear to have a primary association with PM or DM. These include the anti-hPMS-1 antibody, the anti-p155/140 antibody, an antibody against small ubiquitin-like modifier activating enzyme (anti-SAE antibody), the anti-caDM140 antibody, and others. The specificities of these autoantibodies have not been studied as extensively as those of traditional MSAs, but they appear to have diagnostic utility. These tests are not yet commercially available.

Myth: Patients with antisynthetase antibodies always have myositis.

Reality: The antisynthetase antibodies are more specific for an underlying connective tissue disease or an autoimmune syndrome rather than for myositis itself. For each of the antisynthetase antibodies, patients have been reported who have the antibody but do not have myositis. However, these patients have had other features of the antisynthetase syndrome such as interstitial lung disease or an inflammatory arthropathy. Antisynthetase antibody testing should be considered in patients whose interstitial lung disease may have an autoimmune basis, even in the absence of evidence of myositis (Tillie-Leblond et al. 2008). This is particularly true if clinical features such as arthritis, Raynaud's phenomenon, mechanic's hands, or fevers are present.

Pearl: Patients with antisynthetase antibodies often present with features other than myositis but may develop myositis later.

Comment: Patients with antisynthetase antibodies do not always develop myositis, but in those who do, myositis may neither be the presenting or the symptom that brings the patient to medical attention (Schmidt et al. 2000). Such patients may present with interstitial lung disease, a syndrome that resembles rheumatoid arthritis, fever or even the rash of dermatomyositis.

Pearl: Certain antisynthetase antibodies are associated with a higher frequency of myositis than are others.

Comment: Although anti-Jo1 antibodies are detected in some patients with interstitial lung disease who do not have myositis (see above), this clinical picture is more common in patients with the non-Jo-1 antisynthetase autoantibodies. The frequency of myositis is lower in patients who are anti-PL-12 (anti-alanyl-tRNA synthetase), anti-OJ (anti-isoleucyl-tRNA synthetase), or anti-KS (anti-asparaginyl-tRNA synthetase) antibody positive (Targoff and Arnett 1990; Targoff et al. 1993; Sato et al. 2007; Hirakata et al. 2007). The frequency of myositis associated with particular antisynthetases may vary with the ethnic population under study (Hirakata et al. 2007).

Myth: Patients who have MSAs should be antinuclear antibody (ANA) positive if an indirect immunofluorescent assay is used.

Reality: Antisynthetases are directed at aminoacyl-tRNA synthetases, which are cytoplasmic in location. Thus, these autoantibodies usually cause cytoplasmic (not nuclear) patterns of fluorescence on indirect immunofluorescent ANA testing. Cytoplasmic staining may or may not be reported by commercial laboratories; thus, patients with myositis and antisynthetase antibodies are often ANA negative. In patients with antisynthetase antibodies who are ANA positive, coexistent autoantibodies may be present in the serum. Patients with anti-SRP autoantibodies also usually demonstrate cyto-plasmic staining upon immunofluorescence testing for similar reasons as patients with an antisynthetases antibody.

Conversely, patients with anti-Mi-2 and anti-PM-Scl autoantibodies should have a positive ANA test. The anti-Mi-2 antibody yields a nuclear speckled pattern, and anti-PM-Scl antibodies cause a combined nuclear and nucleolar pattern. Anti-p155/140 antibodies usually cause a nuclear speckled pattern, but is less consistent and usually lower in titer.

Pearl: The finding of diffuse cytoplasmic immunofluorescence on ANA testing can be a clue to the presence of antisynthetase or anti-SRP autoantibodies.

Comment: In a patient who has clinical manifestations of an inflammatory myopathy, the finding of a cytoplasmic pattern by indirect immunofluorescence is an indication for obtaining a more thorough analysis for potential MSAs and MAAs. Antiribosomal P antibodies can also give this pattern.

Pearl: Many patients with myositis do not have a myositis-specific autoantibody (MSA).

Comment: Only about 30–40% of patients with DM or PM have antisynthetase, anti-SRP, or anti-Mi2 autoantibodies. By testing for more recently described antibody specificities (see Table 18.1), the frequency of autoantibody identification in these patients increases to greater than 50%. Although a percentage of myositis patients have MAAs, some patients with myositis have no currently identifiable autoantibodies (MSA or MAA) by either commercial or investigational testing.

Table 18.1 Myositis-specific autoantibodies

One study that employed multiple assay techniques in a group of 100 patients detected MSAs or MAAs in 80% of the cohort (Koenig et al. 2007). Although numerous antibodies and combinations of antibodies were found, the study did not include detection of recently described antibodies known to be associated with myositis so the 80% figure may be somewhat low.

Myth: Mechanic's hands are specific for the antisynthetase syndrome.

Reality: Mechanic's hands, the cracking and/or fissuring of the lateral and palmar aspects of the fingers, are associated with the antisynthetase syndrome (see Fig. 18.1d). However, mechanic's hands can occur with other autoantibodies, e.g., anti-PM-Scl antibodies (Oddis et al. 1992).

Not all roughened hands are mechanic's hands. This find-ing must be distinguished from psoriasis, dyshydrotic eczema, and simple calluses.

Myth: All patients with anti-SRP antibodies have a severe myopathy and a disease course characterized by treatment refractoriness.

Reality: Most studies note that anti-SRP patients have more severe weakness than myositis patients without this antibody (Kao et al. 2004; Miller et al. 2002) and some have a rapidly progressive and relatively treatment-resistant course (Love et al. 1991). However, some anti-SRP antibody positive patients are more treatment-responsive and do well with glu-cocorticoids and other immunosuppressive agents (Hengstman et al. 2006; Kao et al. 2004).

Pearl: Patients with anti-SRP autoantibody frequently have less lymphocytic inflammation and relatively greater myofi-ber necrosis on their muscle biopsy.

Comment: The muscle biopsy in patients whose myositis is associated with antibodies to SRP often demonstrates a necrotizing myopathy with little or no inflammation (Dimitri et al. 2007; Hengstman et al. 2006; Kao et al. 2004; Miller et al. 2002). The lack of the classic inflammatory changes of myositis may lead to difficulty with diagnosis. The presence of a necrotizing myopathy and severe muscle weakness should suggest the diagnosis of SRP-associated PM, particularly in the presence of a cytoplasmic pattern on ANA testing (see above). Patients with anti-SRP antibodies rarely have the cutaneous findings of DM.

Pearl: Patients with antisynthetase or anti-PM-Scl autoanti-bodies can have a significant arthropathy.

Comment: Arthritis is found in up to 90% of patients with the antisynthetase syndrome (Love et al. 1991) and is the presenting feature in some patients, leading to a diagnosis of rheumatoid arthritis before other features of the syndrome become evident (see above). The arthritis is not usually erosive, but it can be deforming (Oddis et al. 1990). Patients with anti-PM-Scl can also have arthritis as part of an overlap syndrome that may also demonstrate features of myositis (either PM or DM) and/or scleroderma.

Pearl: The myositis associated with anti-PM-Scl and anti-U1RNP tends to be milder and easier to treat than the myo-sitis associated with antisynthetase and anti-SRP autoantibody subsets.

Comment: The myositis associated with anti-PM-Scl antibodies often occurs in overlap with scleroderma. These patients have milder and more responsive myositis than other autoantibody subsets (Jablonska and Blaszczyk 1999) and respond to lower doses of glucocorticoids than are usually used in myositis. Similarly, patients with myositis and the U1RNP autoantibody generally respond well to lower doses of glucocorticoids and have less long-term morbidity related to their myopathy when compared to the generally poor outcomes seen in myositis patients with antisynthetase and anti-SRP autoantibodies.

Pearl: The presence of anti-p155/140 antibodies and the absence of other MSAs or MAAs are associated with an increased risk of malignancy in adult DM.

Comment: Three studies have found an increased frequency of cancer in adult DM patients who have an autoantibody that immunoprecipitates 155 and 140 kD proteins (Chinoy et al. 2007; Kaji et al. 2007; Targoff et al. 2006). The group with cancer-associated myositis also has a low frequency of other MSAs and MAAs. When used together, these features are helpful in assessing the likelihood of cancer in patients with DM (Chinoy et al. 2007). Unfortunately, testing for this “doublet” is not commercially available and can only be done in research laboratories specializing in the testing of MSAs and MAAs.

18.6 Imaging

Pearl: Magnetic resonance imaging (MRI) findings may distinguish PM from IBM.

Comment: MRI of the thighs with T1 and short tau inversion recovery (STIR) sequences can be helpful in distinguishing PM from sporadic IBM (sIBM) (Fig. 18.4). PM is characterized by isolated inflammation that is symmetrical and generally favors the posterior muscle group. IBM is more likely to be asymmetric with fatty replacement and to involve muscles of the anterior thigh and more distal musculature (Dion et al. 2002).

Fig. 18.4

Axial STIR and T1-weighted MRI images through the mid-section of the thighs of two patients — one with polymyositis (a) (top left and (b) top right), the other with inclusion body myositis (c) bottom left and (Fig. 18.4d bottom right). Note the widespread inflammation and atrophy in all musculature in inclusion body myositis, particularly intense in the anterior muscle group. Polymyositis tends to show inflam-mation and atrophy in a fascial distribution (Figure courtesy of Dr. Mark Gourley)

18.7 Inclusion Body Myositis

Myth: The presence of rimmed vacuoles on muscle biopsy is diagnostic of IBM.

Reality: Although rimmed vacuoles are a characteristic pathological feature in IBM, they may also occur in other neuromuscular disorders, such as distal myopathies, ocu-lopharyngeal myopathy, PM, rigid spine syndrome, congenital myopathies, limb girdle muscular dystrophies, and various neurogenic diseases. The patient's clinical features, the full pathologic picture, the response to therapy, and the overall disease course are all critical components in establishing the diagnosis of IBM. Similarly, the classic finding of rimmed vacuoles in the muscle biopsy of patients with IBM may require repeated biopsies over time.

Myth: Dysphagia is less common in patients with IBM than DM and PM.

Reality: When dysphagia is found in a patient with an inflam-matory myopathy, IBM is the most likely diagnosis. In a study of 62 patients with IIM-associated dysphagia, 42% had IBM, 29% had DM, 15% had PM, and 15% had overlap syndromes (Oh et al. 2007). The dysphagia of IBM is reported by the patient as feeling like a “blocking sensation” with swallowing. It is often associated with the findings of cri-copharyngeal spasm or achalasia on cinesophagram studies.

Pearl: The presence of a foot drop in a patient with “refractory PM” is IBM until proven otherwise.

Comment: Although distal weakness may occur in the IIMs, this is often in the setting of severe and/or chronic PM or DM. However, IBM is associated with both distal and asymmetric muscle weakness as well as muscle atrophy. The find-ing of a foot drop (which may be subtle), manifested by weakness of the ankle dorsiflexors should lead the clinician to consider IBM. This may be unilateral but may be bilateral and variable in severity between both lower extremities.

18.8 Treatment

Myth: Many cases of PM are refractory to immunosuppres-sive therapy.

Reality: This statement is true in cases associated with anti-SRP autoantibodies. However, many “steroid-refractory” PM cases are in fact mimickers of PM. Common mimickers of PM are IBM, muscular dystrophies, mitochondrial or metabolic myopathies, and drug-induced syndromes, the prime example of which is a statin myopathy.

Myth: Exercise is contraindicated in patients with inflamma-tory myopathy during the initial phase of treatment.

Reality: A supervised exercise program is a necessary prescription when treating patients with an inflammatory myo-pathy. The long-held belief that exercise harms patients who have active myositis has been disproved by studies demonstrating benefits in strength, improvements in quality of life, and the absence of muscle disease exacerbations when an appropriately structured exercise program is initiated (Alexanderson et al. 2007). The program should be supervised and instituted in a graded manner so as not to cause muscle pain or worsening weakness.

Pearl: Combination therapy with methotrexate and azathio-prine may be effective in the treatment of refractory myositis when either agent alone is ineffective.

Comment: Although methotrexate or azathioprine in conjunction with glucocorticoids is often at least partially effective in the treatment of myositis, some patients are refractory to either methotrexate or azathioprine alone. The combination of oral methotrexate and azathioprine has evidence-based support for its use in refractory myo-sitis, showing benefit in some patients who previously demonstrated an inadequate response to either methotrex-ate or azathioprine alone (Villalba et al. 1998). Clinicians should consider combination therapy in myositis in a fashion similar to that utilized in other connective tissue diseases.

Pearl: Clinical improvement in muscle weakness lags behind the response in the serum CK and an increase of the serum CK often predates a flare of myositis.

Comment: Although the serum CK should not be used as the only determinant of treatment in patients with myositis (see above), it can provide useful clues in the management of myositis. Many times patients will continue to complain of some degree of muscle weakness even though their CK has normalized. They should be reassured that the clinical response to therapy lags behind the biochemical response and that with continued glucocorticoid tapering (and the maintenance of other immunosuppressive therapy, as appropriate), their muscle strength will likely improve. Similarly, patients who are clinically stable but demonstrate a rising CK from the normal range to elevated values may be headed for a disease flare. Although the clinician would not want to simply increase immunosuppressive therapy in such instances, he/she should carefully monitor such patients for an impending disease flare.

Myth: The presence or absence of peripheral eosinophilia helps distinguish methotrexate lung from other causes of interstitial lung disease.

Reality: The initial cases reported of methotrexate lung described peripheral eosinophilia (Whitcomb et al. 1972). More comprehensive studies performed subsequently, however, reveal that eosinophilia is a nonspecific finding found in only about one-third of the cases of methotrexate lung.