Polymyositis and dermatomyositis: Disease spectrum and classification

Abstract

Muscle inflammation and weakness are the key features of idiopathic inflammatory myopathies (IIMs). In addition IIMs are frequently associated with cutaneous and pulmonary involvement. In clinical practice the three common inflammatory myopathies we come across are polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). The Bohan and Peter criteria combine clinical, laboratory, and pathologic features to define PM and DM. They did not recognize inclusion body myositis (IBM) or other inflammatory myopathies, such as granulomatous and eosinophilic myositis. Thus the disease spectrum is wide and IIMs are a heterogeneous group of autoimmune disorders. To address these issues in this article we have discussed the currently developing newer classifications of IIMs.

Polymyositis and Dermatomyositis

Polymyositis (PM) and Dermatomyositis (DM) are autoimmune myopathies characterized by inflammation and weakness of proximal muscles with extra muscular manifestations.[1] In DM there is muscle weakness associated with skin rash. Although both these disorders share some common clinical and histological features like muscle weakness, inflammatory infiltrates on muscle biopsy, but they have certain differences both in terms of presentation and patho-physiology.[1] Involvement of skin is the primary clinical feature, which distinguishes DM from PM .[1]

Historical Aspect of these Diseases

Myositis was documented in 1863 by Wagner in a patient with significant cutaneous findings.[2] Later on, it has been reported that inflammatory myopathies can also occur in the absence of skin involvement.[3,4] In 1891 the term Dermatomyositis was coined by Unverricht to describe patients with dermatological findings and myopathy.[5] The diagnostic criteria of these diseases were published by Bohan and Peter in 1975.[3]

Pathophysiology of PM and DM

Patients with PM and DM usually presented with sub acute or chronic onset of symmetrical proximal muscle weakness, often associated with high serum creatinine kinase levels. In electromyography and magnetic resonance imaging (MRI) both diseases show overlapping features. Despite these overlapping features these two diseases can be distinguished from one another by histological features on biopsy.[1] From the immunological point of view these two diseases are different. Dermatomyositis is humorally mediated disease whereas polymyositis is T cell mediated disease.[6]

Histological Findings of DM Muscular Tissue

In DM, the histopathology of muscles indicates primary involvement of microcirculation mediated by humoral processes associated with secondary ischemic changes of muscle fibers.[7–9] The hallmark feature of DM is presence of peri-fascicular atrophic regenerating and degenerating myofibers, which has been resulted from destruction of capillaries of this region.[1] It has been proposed that depletion of capillaries induces localized hypoxia and injury to the myofibers.[7] In fact this loss of capillary and abnormal morphology is an early feature of DM and can occur in the absence of inflammatory infiltrates.[10,11] But one recent study showed that in both PM and DM there is early capillary loss so it is not disease specific.[12] In different studies from DM muscle tissues have demonstrated that deposition of the C5b-9 membrane attack complex (MAC) on endothelial cells and the presence of abnormal tubo-reticular structures within the smooth endoplasmic reticulum of endothelial cells occur before the depletion of capillaries.[11,13] Another characteristic feature of DM is presence of peri-vascular inflammation in the muscle. In this inflammatory collections B cells predominates over CD4⁺T cells.[14] Greenberg et al. have reported that most of the CD4⁺ T cells in the DM muscle biopsies are plasmacytoid dendritic cells, which are potent source of IFN-α. Therefore genes induced by IFN-α are highly expressed in muscle biopsies of DM patients compared with other inflammatory myopathies.[15] Moreover, it has been found in other studies that in periphery IFN-α/β inducible gene expression correlate with disease activity of DM.,[16,17]

Histological Findings of PM Muscular Tissue

In PM the characteristic feature is presence of CD8⁺ T cells and macrophages in the myofibers.[18] Compared with healthy muscles, MHC-I is up regulated in myofibers of PM.[19–21] The expression of MHC-I on myositis muscle suggest that these cells may be killed by CD8⁺ T cells which contain perforin, a pore-forming protein that mediates the entry of cytotoxic proteases and calcium into target cells. In confocal microscopic studies it has been found that these perforin-containing granules are oriented toward muscle fibers, consistent with a cytotoxic mechanism of cell death in PM.[22] Although MHC-I has been proposed to mediate cell death in PM, but it is also expressed in DM patients mainly on perifascicular fibers.[21] In one study Fasth et al. have reported that in muscles of patients of PM and DM, the main effector T-cell subset is CD28^null T-cells, which are resistant to apoptosis and thus may be responsible for recurrence of disease following treatment.[23]

Histological Finding in Skin of DM Patients

Skin biopsies of DM lesions demonstrate sparse infiltrate of inflammatory cells at the dermo-epidermal junction.[24] This inter-phase dermatitis resembles histopathological features of cutaneous lupus. The dermal infiltrates consists of activated T cells and there is deposition of immune complex along the vessel walls of the dermis.[25,26] This finding along with muscle pathology findings suggests that blood vessels may be the primary target of immune response in DM. It has also been shown that in DM patients there is increase in Ki-67 positive keratinocytes and decreased number of Bcl-2 positive cells in the basal layer of epidermis suggesting increase proliferation and abnormal apoptotic pathway in skin of DM patients.[1]

Myositis Associated Auto-antibodies

Like other auto-immune diseases, in PM and DM also strong association of auto-antibodies with distinct clinical phenotypes is found. These auto-antibodies have been classified into myositis-associated autoantibodies (MAAs), which can be found in patients with other connective tissue diseases, and myositis specific antibodies (MSAs), which are found primarily in patients with myositis.[27] The exact role of these auto-antibodies in the disease pathology is not clear.

In 1980, auto-antibodies against the histidyl-tRNA synthetase (anti-Jo-1) were first described and are the most common MSAs.[28] In 25–30% of myositis patients anti-Jo-1 may be present.[29] Patients with these antibodies are associated with a unique clinical syndrome including myositis, interstitial lung disease (ILD), nonerosive arthritis, fever, and characteristic hyperkeratotic lesions along the radial and palmar aspects of the fingers known as “mechanic's hands”.[30,31] Among the Jo-1 positive patients, 90% may have muscle disease.[1] There are some mixed results about the association of anti-Jo-1 and PM/DM. In couple of studies it has been found that anti-Jo-1 is more associated with PM than DM.[32,33] In contrast, another study found that anti-Jo-1 is almost equally present in patients with PM and DM.[34] These differences may be attributed to different demographic and referral patterns. Moreover from few studies it has been revealed that titers of anti-Jo-1 are correlated with disease activity.[30,35–37] In one study by Stone et al. it has been found that in 81 patients with positive anti-Jo-1, there was modest correlation between auto-antibody titer, creatinine kinase level, muscle and lung involvement.[37] Therefore serial anti-Jo-1 titer follow up in an individual may be a good indicator of disease activity.

Another important auto-antibody is anti-Mi-2, which was first described in a patient with DM in 1960.[38] Later on it was found that by immunoprecipitation technique, this auto-antibody is present in 20–30% of DM patients whereas few patients with PM are positive for this auto-antibody.[39–42] However, studies using ELISA detection assay found significant number of Mi-2 positive cases in patients with PM.[43–45] This may be due to high false positive result with ELISA. Patients of DM with anti-Mi-2 are more susceptible to have severe form of cutaneous manifestations like heliotrope rashes, shawl rashes over the upper back and neck and cuticular over growth. Additionally, DM patients with anti-Mi-2 positive has a more favorable prognosis, respond better to steroid treatment and low incidence of malignancy compared with other DM patients.[40,42,43,46,47] A correlation between surface UV radiation intensity and development of anti-Mi-2 antibody in patients with DM has been established. At lower latitudes, like in Guatemala City where the UV exposure is more, 60% of DM patients are anti-Mi-2 positive whereas in Glasgow where the UV exposure is relatively less, only 6.7% are anti-Mi-2 positive.[48] In a study, Casciola-Rosen et al. showed that Mi-2 protein levels were found to be relatively low in muscles of healthy individuals and patients with PM whereas DM patients have increased expression of Mi-2.[1,49]

In 1986, Reeves first described the presence of another auto-antibody, anti-signal recognition particle auto-antibodies (anti-SRP) in a “typical polymyositis” patient.[50] There are few reports available on this antibody and its association with PM/DM. In one study, Targoff showed that this antibody is present in 4% of PM/DM patients. These patients did not have DM rashes or overlap syndrome, but they have severe muscle disease.[51] Subsequently it has been found that these (anti-SRP positive) patients have severe and rapidly progressive muscle disease, which responds to steroid initially, and their biopsy showed much less lymphocytic infiltrates than seen in patients with PM/DM.[52] In other studies involved, relatively larger cohort also established that patients with anti-SRP positive have severe muscle disease and lacks typical histological features of PM/DM.[53,54]

Another auto-antibody, anti-155/140 is highly specific and found in 13–21% of patients with DM.[55,56] Moreover, patients with this antibody had higher rate of malignancy (71%) than patients of DM negative (11%) for this antibody.[55] Patients with anti-155/140 had lower rate of interstitial lung disease than other patients of DM.[56] In one study on Japanese patients, Kaji et al. showed that patients with this antibody were more likely to have heliotrope rash and Gottron's sign than other patients of DM[55] but in another study no such differences were found.[56] This disparity may be due to difference in ethnicity of the study group. Moreover, this antibody was found in patients with juvenile form of DM, where other MSA are rare to find.[57]

Diagnostic and Classification Criteria of Inflammatory Polymyositis

Bohan and Peter criteria are most widely used for diagnosis of polymyositis and dermatomyositis. The original Bohan and Peter criteria proposed in 1975, included the following features:[3,58]

1. Symmetric proximal muscle weakness

2. Typical rash of DM (a distinguishing feature for DM and PM)

3. Elevated serum muscle enzymes

4. Myopathic changes on electromyography

According to the Bohan and Peter diagnostic criteria for a definite diagnosis of DM it requires four criteria (including rash) and for a definite diagnosis of PM it requires four criteria (without rash). Probable disease comprises three criteria (including rash) for DM and three criteria (without rash) for PM. Possible disease requires two criteria (including rash) for DM and two criteria (without rash) for PM.

The most commonly used clinical classification of inflammatory idiopathic polymyositis was also proposed by Bohan and Peter.[3,58] Their classification system was (i) primary idiopathic PM, (ii) primary idiopathic DM, (iii) juvenile DM, (iv) PM or DM with malignancy, and (v) PM or DM with associated collagen vascular diseases. However, they did not recognize inclusion body myositis (IBM) or other inflammatory myopathies, such as granulomatous and eosinophilic myositis. When this criteria was formulated, tests for myositis specific auto-antibodies were not available. To overcome these limitations different classification criteria have been proposed for DM and PM.[59–61]

A classification criteria scheme has been proposed by an international workshop of myositis experts focused on criteria for the inclusion of patients in clinical trials.[60] It was stressed strongly that these criteria should be validated and tested for reliability in prospective studies in order to allow further improvements in the future. This classification exclude myositis associated with either a connective tissue disease or malignancy but included the following categories:

1. Inclusion body myositis

2. Definite PM

3. Probable PM

4. Definite DM

5. Probable DM

6. Amyopathic DM, also called dermatomyositis sine myositis

7. Possible dermatomyositis sine dermatitis

8. Nonspecific myositis

Clinicians widely accept that modern-day histopathology and genetic techniques need to exclude IBM, hereditary and other myopathies when applying the Bohan and Peter criteria. Currently newer classifications are on development based on autoantibody subgroups[60] or on muscle histopathology.[61] These newer classification systems intend to provide insight in respect to disease prognosis as well as response to treatment compared to the Bohan and Peter criteria.