Review of the classification and assessment of the cutaneous manifestations of the idiopathic inflammatory myopathies
Published Web Locationhttps://doi.org/10.5070/D30f26q4rm
Review of the classification and assessment of the cutaneous manifestations of the idiopathic inflammatory myopathies1. Division of Dermatology, Department of Medicine, Georgetown University Hospital, Washington, DC
Elizabeth M Dugan1, Adam M Huber2, Frederick W Miller3 Lisa G Rider3, for the International Myositis Assessment and Clinical Studies (IMACS) Group4
Dermatology Online Journal 15 (2): 2
2. IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada
3. Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, DHHS, Bethesda, Maryland. email@example.com
4. Contributors to this photoessay listed in the appendix.
See accompanying review article Photoessay of the cutaneous manifestations of the idiopathic inflammatory myopathies
The idiopathic inflammatory myopathies (IIM) are a group of rare, immune-mediated diseases which affect skeletal muscle, characterized by weakness, impaired physical function and reduced endurance. Cutaneous features are integral to the clinical presentation of several of these disorders, including dermatomyositis (DM), juvenile DM, paraneoplastic DM, DM overlapping with features of other connective tissue diseases, amyopathic DM (ADM) and drug-induced DM. Patients with polymyositis (PM) also frequently present with a variety of cutaneous manifestations, although none are considered characteristic lesions of DM. In all of these IIM subgroups, consideration of the cutaneous manifestations is important for the accurate and timely diagnosis, prediction of outcome and for the ongoing evaluation of response to treatment. This is particularly true when the cutaneous features precede the onset of skeletal muscle, lung or other systemic involvement.
Although skin findings must be appreciated within the overall context of the IIM, it is clear that cutaneous manifestations warrant separate recognition and evaluation, and may require separate treatment [1, 2, 3, 4]. The presence of pathognomonic or characteristic skin lesions may be the key to making the diagnosis of DM (see accompanying Photoessay of the Cutaneous Manifestations of the Idiopathic Inflammatory Myopathies). This is especially important when patients present with isolated cutaneous findings [5, 6]. Cutaneous manifestations may precede or follow the onset of muscle involvement by months or even several years, and may be the most active or difficult feature of the IIM to manage. In addition, cutaneous lesions can have a significant negative impact on patients' quality of life. Hundley et al. evaluated the impact of active cutaneous symptoms of DM on quality of life in 71 adults with DM or ADM and found that the impact on quality of life was greater than for patients with psoriasis, atopic dermatitis or vitiligo . Pruritus, an under-recognized symptom of DM, is a large component of the impact on quality of life . In one study by Peloro et al., pruritus occurred in 38 percent of children with juvenile DM .
The presence of chronic cutaneous lesions of DM can also be very problematic for patients. In children, calcinosis, which is associated with the duration of skin disease , can result in pain, skin ulceration, superimposed infection, scarring, and if marked, limited joint range of motion and physical dysfunction. Lipoatrophy, most commonly seen in juvenile DM, can result in dramatic changes in appearance, and may be associated with significant metabolic changes, including Type II diabetes and insulin resistance. There are significant negative psychological consequences to these lesions, particularly if located in cosmetically sensitive sites. Finally, the presence of persistent cutaneous pathology is postulated to represent ongoing systemic vasculopathy [9, 10] which may be associated with serious and potentially life-threatening systemic
In this review, we will consider recent advances in the recognition of autoantibody-associated phenotypes, with an emphasis on findings that are relevant to the understanding of skin disease. Malignancy-associated DM, drug-induced IIM, recent advances in the understanding of the pathogenesis of the cutaneous manifestations of the IIM and the assessment of skin disease in the IIM will also be reviewed. This work will not include clinical features of the IIM or detail specific cutaneous lesions, as these issues have been recently reviewed [1, 2, 3, 6], and the accompanying photo-essay will address the specific cutaneous manifestations of the IIM.
Myositis Specific Autoantibodies and their Associated Cutaneous Manifestations
The presence of autoantibodies has been well described in the IIM. Several of these represent myositis-specific autoantibodies (MSA), and are associated with well-described clinical subsets in adult patients. Cutaneous features can play an important role in defining these clinical phenotypes, particularly in adult patients (Table 1) [11, 12]. Studies have shown that children with IIM have the same MSA as found in adults with IIM, but they are seen less frequently [13, 14].
Anti-Mi-2 Autoantibodies and Classical DM
Autoantibodies to Mi-2, a MSA directed against a nuclear helicase, are typically found in 15-20 percent of DM patients, and have been associated with a relatively good prognosis, a reduced risk of interstitial lung disease, and a more reliable response to therapy with fewer exacerbations [13, 15]. Adult patients in this subset present with classic features of DM including pathognomic heliotrope and Gottron's papules. Distinguishing cutaneous findings for this autoantibody-associated clinical subset include the V-sign, the shawl sign, and cuticular overgrowth. Juvenile DM patients with anti-Mi-2 autoantibodies have also been reported, and they share some clinical features with adults, including heliotrope rash and Gottron's papules. Notably, these children usually demonstrate a monocyclic course and a good response to treatment [13, 14]. When anti-Mi-2 antibodies are determined by enzyme-linked immunosorbent assay, specificity for DM appears to be reduced.
Anti-synthetase Autoantibodies and the Anti-Synthetase Syndrome
The aminoacyl-tRNA synthetases participate in the binding of amino acids to the corresponding tRNA, a critical step in protein synthesis. There are several MSA's with specificity for these unique synthetase proteins, including anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-KS and anti-Zo . Patients with anti-synthetase autoantibodies have similar clinical features including fever, polyarthritis, Raynaud's and interstitial lung disease, which is known as the "anti-synthetase syndrome" . Mechanic's hands are the most specific cutaneous marker of anti-synthetase syndrome syndrome in adults and consist of hyperkeratosis, scaling and fissuring of the fingers and palms. The clinical finding of mechanic's hands increases the likelihood that interstitial lung disease, the most insidious complication of the anti-synthetase syndrome, is present. Although found most commonly in the setting of the anti-synthetase syndrome, mechanic's hands can also be seen in cases of PM, classic DM  and ADM  not associated with anti-synthetase autoantibodies.
Several children with juvenile DM and anti-aminoacyl-tRNA synthetase autoantibodies have also demonstrated features of the anti-synthetase syndrome. However, the presence of mechanic's hands is variable. One reported juvenile DM patient presented with acral non-healing cutaneous ulcers .
Even in the absence of the full anti-synthetase syndrome, the finding of anti-synthetase autoantibodies is important. Occult interstitial lung disease is much more common in these patients (95% vs. 45% in one recent report), as are treatment resistance and disease recurrences .
Cutaneous Manifestations Linked to the Myositis Associated Autoantibodies
Several myositis-associated autoantibodies (MAA) have also been described in both in adults and children with IIM. These include anti-PM-Scl, anti-U1RNP and anti-Ro, which are more commonly seen in patients with myositis overlapping with other connective tissue diseases or in patients with IIM and overlap features [14, 20]. In particular, anti-PM-Scl autoantibody may be seen in patients with sclerodermatous skin pathology, including en coup de sabre, severe Raynaud's and sclerodactyly, which can occur with or without more typical DM skin lesions. Thus, this MAA may be a marker for later progression to scleroderma or scleroderma-like disease . Anti-PM-Scl autoantibodies are directed against an 11-16 polypeptide nucleolar complex.
Autoantibodies to p155
A new MAA has recently been identified in both adults and children with IIM. The anti-p155 autoantibody is directed against a 155-kd protein preliminarily identified as transcriptional intermediary factor 1-gamma . In a study of 244 IIM patients, anti-p155 autoantibody was present in the sera of 29 percent of juvenile DM patients, 21 percent of adult DM patients, 33 percent of juvenile and 15 percent of adult connective tissue disease associated myositis, and 75 percent of malignancy associated myositis, all of whom had features typical for DM . Another study found anti-p155 in 23 percent of juvenile DM patients . This autoantibody was not seen in the sera of adult or juvenile PM, and was present in the serum of only in 1 patient with systemic lupus erythematosus of 138 non-IIM patients tested (including 49 lupus, 18 scleroderma, 41 non-inflammatory myopathies and 22 healthy controls).
Cutaneous features seen more frequently in patients with the anti-p155 autoantibody include skin ulcers , subcutaneous edema , erythroderma and generalized lipodystrophy , all of which signify more serious underlying systemic disease activity. The V-sign rash, the shawl-sign rash and Gottron's papules or sign are also commonly observed, although this may be related to their associations with DM, rather than being distinct to the p155 autoantibody. . The risk of interstitial lung disease appears to be lower in patients with the p155 autoantibody than in other subgroups of IIM . In adults with DM, anti-p155 autoantibody appears to be strongly associated with an increased risk of malignancy .
Autoantibodies to CADM-140 in ADM
Recently, an autoantibody to a 140 kD protein was described which has been named CADM-140 because of its possible specificity for ADM . ADM (also called clinically amyopathic DM and DM sine myositis) has been described in both adults and children, and presents with classic cutaneous features of DM without concomitant muscle weakness, elevation in muscle enzymes or evidence of muscle involvement by biopsy, magnetic resonance imaging or electromyography [27, 28]. Definitions of ADM require a duration of cutaneous manifestations for at least 24 months without the development of muscle involvement [28, 29].
In a recent study, 8 of 42 patients with DM were found to have autoantibodies to a 140-kd protein and all had ADM. It was not detected in other DM patients or in patients with other connective tissue diseases. This subset of patients appears to be at risk of developing rapidly progressive interstitial lung disease, which may be seen in up to 13 percent of adults with ADM , even in the absence of the anti-synthetase autoantibodies. A systematic literature review did not identify a similar risk of interstitial lung disease in children with ADM . The CADM-140 autoantibody is distinct from the p155 autoantibody (which also precipitates a 140-kd protein) .
A substantial number of patients (13-26%) with ADM later develop overt muscle disease [27, 28]. There are currently no effective clinical or serological predictors for this outcome [27, 28]. ADM has been previously reviewed in detail [27, 28, 30].
Autoantibodies to MJ
Preliminary work has identified another 140 kD autoantibody in the serum of as many as 21 percent of juvenile DM patients, which is distinct in specificity from the p155 autoantibody . This is known as anti-MJ and targets a nuclear matrix protein NXP-2 . Calcinosis may be more frequent in patient with the MJ autoantibody.
In summary, MSA and MAA are frequently associated with defined phenotypes manifesting cutaneous features which may be useful in classifying the IIM and predicting complications and outcomes. For this reason, it has been recommended that evaluation of adult IIM patients include these autoantibodies . The role of this testing is less clear in children with IIM , but may be helpful in patients with refractory disease or those matching the clinical phenotypes associated with these autoantibodies. Testing is most reliable when immunoprecipitation methods are used, and only a few laboratories in the country use this methodology.
DM and Cutaneous Manifestations Associated with Malignancy
There is a clear association between DM in adults and malignancy. A population-based study using national databases from the Scandinavian countries documented the rate of malignancy to be as high as 30 percent in adults with DM  [they should really list odds ratio and note that risk is greatest in women over 50 etc.]. Similar results have been reported in recent studies [35, 36]. In patients with adult DM, malignancy onset most often occurs within one year of the diagnosis of DM . As a result, the clinical presentation with DM is, in and of itself, a marker for potential underlying malignancy. It is recommended that an age- and gender-appropriate work-up for malignancy be performed for all newly diagnosed adults with IIM. Additional factors to consider may include ethnicity, environmental exposure (such as smoking or occupation) and other local factors. The association of cancer with other forms of IIM, such as PM, IBM or ADM is less clear, but it is likely that a somewhat lower but still increased risk is present [34, 36]. One study found that 14 percent of patients with ADM had an associated malignancy . Underlying malignancies are twice as frequent in females than in males . Age greater than 50 years is an additional risk factor for associated malignancy .
In children with IIM, there have been case reports documenting the co-existence of IIM and malignancy . One study, which examined a population-based cohort of both adults and children with IIM found an increased risk of malignancy for children with IIM, but the numbers were very small with only 2 malignancies observed, making it difficult draw conclusions . Generally, malignancies in children with IIM are rare, so that an evaluation for malignancy is not routinely performed at the time of diagnosis of IIM in children, but is considered in patients with atypical rashes or other signs of malignancy, such as the presence of lymphadenopathy, profound weight loss, or a palpable mass.
Attempts have been made to identify specific cutaneous lesions of IIM and DM in particular that may signal the presence of underlying malignancy. Cutaneous ulceration or necrosis and leukocytoclastic vasculitis, although relatively rare in adult DM, have been shown to be associated with malignancy in some reports [41, 42]. Erythroderma has been described as a marker of malignancy in DM . The presence of pruritus has also been suggested as a marker of malignancy . However, given the frequency of pruritus as a symptom in patients with both adult and juvenile DM [6, 7] its specificity is unclear. Acquired ichthyosis, a paraneoplastic cutaneous sign, has also been reported in the setting of DM and underlying malignancy .
As noted above, the anti-p155 autoantibody may be associated with malignancy, but this autoantibody is also seen in other forms of IIM . Elevation of the serum tumor marker CA-125 in DM has also been associated with an increased risk of malignancy .
Cutaneous Features of Drug Induced IIM
A number of medications can be associated with the development of findings that mimic the IIM, including muscle involvement and DM-like cutaneous features such as photosensitive erythema, heliotrope rash and Gottron's papules . This is most commonly described with statin cholesterol lowering medications and penicillamine . Other drugs include, but are not likely limited to, penicillins, sulfonamides, terbinafine, isoniazid, tamoxifen, chlorpromazine, antazoline, clemizol, phenylbutazone and minocycline. Interferon-α2B and the anti-TNF biologic agents have been reported to cause DM-like signs and symptoms [2, 46, 47, 48, 49].
Several drugs have been associated with cutaneous lesions resembling DM without muscle involvement, analogous to drug-induced systemic lupus erythematosus, which predominantly induces photosensitizing cutaneous manifestations, but rarely affects the kidney and other vital organs. The best described of these is hydroxyurea , but a variety of other medications have also been associated with similar findings including etoposide, cyclophosphamide, diclofenac, acetylsalicylic acid, penicillamine, imatinib mesylate and the bacille Calmette-Guérin vaccine [2, 47, 51, 52]. An additional case of ADM has been reported to be associated with fibrate therapy . Studies evaluating an association between autoantibodies and drug induced DM have not been undertaken.
A recent review of case reports of drug- induced DM  identified 70 cases, with half being secondary to hydroxyurea and lacking muscle involvement. They found that 57 percent had Gottron's papules and 36 percent had heliotrope rash (17% had both). An additional 10 cases (14%) had other cutaneous lesions characteristic of DM, including periungual erythema, violaceous erythema on extensor surfaces and poikiloderma in a sun-exposed distribution. Another review of 14 patients with statin-associated disease described the presence of photo distributed erythema, heliotrope rash, Gottron's papules and periungual telangiectasia in the majority of patients . Case reports concerning other agents have described similar lesions. It does not appear that there are cutaneous features which can distinguish patients with drug-induced myositis from IIM, given that the skin findings resemble those of typical IIM. The importance of taking an appropriate history and having a high index of suspicion cannot be overemphasized.
Endocrinopathy in Association with Juvenile DM: Lipodystrophy, Insulin Resistance and Acanthosis Nigricans
Acquired lipodystrophy (or lipoatrophy) has recently been recognized as an important cutaneous feature in DM . In this condition, patients lose subcutaneous fat in a localized (focal), partial (mainly extremities) or generalized pattern, due to the loss of mature adipocytes . This is seen most frequently in juvenile DM, and may be delayed several years after disease onset. Localized lipodystrophy may affect the face, giving a "sunken cheeks" appearance and making the masseter muscles more prominent. Focal areas of subcutaneous fat loss may be seen, particularly at sites of calcinosis . Partial and total lipodystrophy often give a more sculpted appearance of the extremities, as the loss of fat makes the muscles more easily defined. Although acquired lipodystrophy is most commonly associated with juvenile DM, it can rarely be seen in adult-onset DM . Lipodystrophy is not seen in association with other forms of IIM, but has been described in other autoimmune illnesses . Single center studies have reported lipodystrophy to affect 10-40 percent of children with juvenile DM, while a larger registry of juvenile DM has estimated the prevalence of acquired lipodystrophy to be 7.9 percent . It has been suggested that the current rate of clinical diagnosis may significantly underestimate the true prevalence .
Lipodystrophy is frequently associated with acanthosis nigricans, which consists of soft, velvety, mildly papillomatous, hyperpigmented, thin plaques, typically at sites with skin folds such as the neck, axillae, inguinal and intergluteal creases, as well as popliteal and antecubital fossae . While this has the appearance of "dirty skin," it cannot be scrubbed off.
While lipodystrophy has cosmetic implications, the main clinical significance is the associated serious metabolic derangements. In the largest study to date, 38 percent of patients with lipodystrophy were found to have impaired glucose tolerance or overt diabetes and 62 percent were found to have elevated fasting insulin values . Elevated levels of triglycerides (47%), elevated serum testosterone, often associated with menstrual irregularities (38%, all female) and evidence of steatohepatitis were also observed . Other studies have documented these features, as well as hypertension [54, 56].
The cause of lipodystrophy is unknown. It has been shown to be associated with joint contractures, calcinosis and a chronic continuous disease course, suggesting that overall disease severity and duration are likely important factors . Panniculitis has been associated with focal lipoatrophy . One study has suggested that younger age at onset of IIM may also be a risk factor .
Pathogenesis of Cutaneous Manifestations of the IIM
Allellic Polymorphisms in the TNF-α-308A Allele, Photosensitivity and Vasculopathy
The last several years have seen considerable advancement of the understanding of the pathogenesis of the IIM which may shed light on skin pathology. One intriguing line of evidence has been the identification of allelic polymorphisms in the TNF-α gene as risk factors for both adult and juvenile DM [57, 58, 59, 60].
Recent advances in the understanding of IIM indicate that photosensitivity plays a role in initiating or exacerbating cutaneous lesions. Such lesions can be precipitated by both ultraviolet-A (UV-A) and UV-B light, from both natural and artificial sources . Photosensitivity in DM patients may be due in part to the TNF-α -308A allele, which is seen with increased frequency in Caucasian adult and juvenile DM patients [59, 61, 62, 63]. The presence of this polymorphism, shared by some patients with subacute cutaneous lupus erythematosus (SCLE) , leads to increased keratinocyte UV-induced apoptosis. Polymorphisms of the TNF-α -308 A allele and other genes involved in apoptosis may also be involved in susceptibility to UV-mediated skin damage in DM [61, 65].
Allelic polymorphisms in the TNF-α gene lead to increased production of TNF-α by peripheral blood mononuclear and muscle cells, suggesting a role for this polymorphism in pathogenesis . The TNF-α -308A allele is associated with disease chronicity in juvenile DM, as well as the development of calcinosis and cutaneous ulcerations [59, 63]. In addition, occlusion of capillaries in muscle biopsies has been associated with the TNF-α -308A polymorphism, and this may be mediated by a corresponding increase in levels of thrombospondin-1, an anti-angiogenic factor which is known to cause smooth muscle proliferation and narrowing of vascular lumens .
Other cytokine polymorphisms are also likely to have a role in the development of certain cutaneous manifestations. For example, the IL-1α-889 CC polymorphism is also a risk factor for the development of calcinosis in patients with juvenile DM .
Vasculopathic changes are important features of IIM
Changes in the nailfold capillaries, including dilatation, occlusion, arboreal loops, hemorrhages and vessel drop-out are well-established in the IIM and in juvenile DM in particular [9, 10, 66, 67, 68, 69, 70]. These changes have been shown to correlate with skin disease activity [9, 10], overall disease activity [69, 70], severity of disease course [9, 66], and untreated disease duration [9, 10]. More recently, it has been shown that in adults with DM, cutaneous blood flow is increased compared to normal controls, even in areas of apparently uninvolved skin . This suggests underlying abnormalities in regulation of capillary blood flow.
The Role of Plasmacytoid Dendritic Cells, Alpha Interferons and Vasculopathic Changes
Plasmacytoid dendritic cells (PDCs) appear to be critically important in the pathophysiology of IIM. These cells, which play an essential role in the response to viral pathogens, have been found in the affected muscle of adult [72, 73] and juvenile DM patients [74, 75]. Of even more interest, PDCs found in normal muscle tissue are immature and scattered through the muscle, while those found in juvenile DM biopsies are mature and localized to areas of mononuclear infiltrates . This suggests that the maturation and localization of PDCs are important in the pathogenesis of IIM. A recent study has demonstrated preferential localization of PDCs in the epidermis of skin biopsies taken from patients with DM , in contrast to the predominant dermal localization of PDCs in cutaneous lupus. This finding supports a site-specific pathogenic role for PDCs in the cutaneous lesion of DM.
Mature PDCs are able to produce large amounts type I interferons which then upregulate a variety of type I interferon-inducible proteins. This has been observed in the skeletal muscle of DM [73, 77] and juvenile DM patients [78, 79]. Of particular interest are interferon-inducible proteins with angiostatic properties, potentially contributing to vasculopathic changes . It has been theorized that the underlying pathology of IIM is related to an unknown insult leading to activation of immature PDCs, which initiates a T-cell mediated inflammation. These conditions lead to PDC maturation and localization to areas of inflammation, resultant production of type I interferons by PDCs, and expression of interferon-inducible proteins on key cellular targets including keratinocytes and cutaneous endothelial cells. This results in and perpetuates an inflammatory and immunologic response manifest as vasculopathic changes .
Microchimerism and Histopathology of the Skin in DM
Recent work in microchimerism has shown that children with JDM are more likely to have chimeric cells (cells present which are genetically distinct from self, related to cell trafficking between mother and fetus), with these cells being found both in muscle biopsies and in the peripheral blood [81-86]. The cells have been found to be mostly B-lymphocytes and dendritic cells . It has been observed that maternally transferred T-cells are reactive against the child's T-cells, implying that these chimeric cells are immunologically active, and may participate in the disease process .
Similarities in the clinical and histopathologic findings of graft-versus-host disease and DM have been described. Poikiloderma is seen in GVHD and in DM, although can also be seen in unrelated conditions such as sun-damage. Histopathologic features of skin biopsies in both conditions can be indistinguishable, characterized by an interface dermatitis, with mild inflammation and apoptotic keratinocytes. In addition, there are similar changes in the microvasculature of IIM, scleroderma and GVHD .
The Role of Complement Mediated Vascular Injury in DM.
Recent studies have focused on characteristic microvascular changes found in both adult and juvenile DM skin biopsies, and the role of vasculopathy in skin lesions, as has been demonstrated in muscle. These changes consist of vascular ectasia, intimal hyperplasia, and endothelial injury of dermal capillaries [87, 88].
Mascaro et al.  demonstrated a role for complement-mediated injury by showing membrane attack complexes (MAC, C5-9) within blood vessel walls of involved skin and muscle. To distinguish DM from lupus erythematosus, Crowson and Magro demonstrated a greater degree of vascular dilatation, endothelial damage, MAC and fibrin deposition and vascular drop-out in adult DM patients compared with SCLE patients using an indirect immunofluorescent technique [90, 91]. Findings were similar between myopathic DM and ADM in their study . These authors believe that a paucicellular interface dermatitis associated with complement- mediated microvascular injury and resultant vessel drop-out are the key histological features of DM, and distinguish it from SCLE.
Evaluation of Skin Disease in the IIM
The evaluation of skin disease in the IIM can be very complex. Individual patients can have many different lesions, with variable severity and varying degrees of activity or damage. This becomes more difficult when patients are assessed over time. Some lesions may improve and others may worsen, and still others may appear or disappear. Dermatologic assessment becomes challenging when comparing skin disease activity or damage between patients or measuring change over time. These issues are relevant to both clinical care and research studies.
The concept of activity and damage is an important component of the assessment of skin disease in the IIM. Skin disease activity is generally defined as reversible features which are directly related to the ongoing inflammatory process, and is assumed to be capable of complete resolution if the underlying inflammation is controlled, but may result in damage if uncontrolled for an extended period of time [92, 93]. Skin disease damage represents persistent cutaneous changes (whether in appearance, structure or function) which are related to previous disease activity or complications of therapy or other processes and are thought to be generally irreversible [92, 93]. Damage may include scarring, atrophic or dystrophic changes. The distinction between activity and damage is an important one, as activity may dictate changes in immunosuppressive or immunomodulatory therapy, whereas damage is less likely to respond to such interventions.
In the past, most studies of IIM focused on muscle-oriented outcomes, including strength and physical function. While this is clearly an important part of the assessment of patients with IIM, we have noted in this review that cutaneous features are important in diagnosing IIM, identifying prognostic subsets and providing an important window to understanding pathogenesis. Skin disease is also an important component of both disease activity and damage, and has a significant impact on patient quality of life. For these reasons, it has become clear in recent years that the assessment of skin disease is important.
Several approaches have been taken to incorporate the assessment of skin disease into the overall assessment of IIM patients (summarized in Table 2). Some global tools incorporate assessment of skin disease with other component of myositis disease activity. The Disease Activity Score (DAS) includes a skin disease activity domain which consists of 10 items for the assessment of skin disease in juvenile DM . These items include presence and severity of erythema, distribution of cutaneous involvement, presence of vasculopathic lesions, and the presence and severity of Gottron's papules. This tool has been shown to exhibit good inter-rater reliability, construct validity, discriminant validity and responsiveness [94, 95]. However, the DAS incorporates a limited assessment of skin disease, combines activity and damage, and to date has been studied only in juvenile DM. The Myositis Disease Activity Assessment (MYOACT) and the Myositis Intention-to-Treat Activity Index (MITAX) include the assessment of skin disease in the IIM and are intended to be used together. The MYOACT assesses a skin global activity score with a 10 cm visual analogue scale, whereas the MITAX evaluates 9 cutaneous manifestations by determining if they have remained stable, worsened or improved over the past month, which is intended to indicate whether a change in treatment is needed . These tools consider skin disease in a global fashion, and do not provide guidance on weighting of different lesions or on severity of lesions. Good responsiveness and reliability for both tools have been reported [95, 96], and to date they have been studied in patients with adult and juvenile DM and PM.
It was recognized that a more comprehensive tool was needed to assess skin disease in the IIM. To address this need, the Cutaneous Assessment Tool (CAT) was developed by a multidisciplinary group of adult and pediatric rheumatologists and a dermatologist, with input from dermatologists expert in the assessment of skin disease in the IIM . The CAT is a 21 item tool which assesses both the presence and severity of activity and damage lesions in DM. It was developed to be comprehensive, semi-quantitative and to include relevant skin lesions seen in both children and adults with IIM, including DM, PM and ADM. It has been shown to demonstrate good inter-rater reliability, construct validity and responsiveness in a large population of juvenile DM [97, 98]. Due to its length and complexity, a shortened version of the CAT has also been developed, which assesses the same 21 lesions for their absence or presence only. This shortened version of the CAT has been shown to have similar reliability, construct validity and responsiveness as the full-length tool .
There are two other tools specifically designed for the assessment of skin disease in the IIM, primarily for the assessment of adult and juvenile DM and ADM. The Dermatomyositis Skin Severity Index (DSSI) was developed by a group of dermatologists and assesses redness, induration, scaliness and surface area of skin involvement, but does not distinguish between different skin lesions of IIM . It was evaluated by a group of rheumatologists and dermatologists in a small number adults and children with DM, and appeared to have good inter- and intra-rater reliability and construct validity. Responsiveness was not assessed . The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), also developed by a group of dermatologists, assesses 16 body areas, scoring each for erythema, thickness, scaling, excoriation and ulceration. Gottron's lesions, periungual changes and alopecia are scored separately . The performance characteristics of this tool have been evaluated in a small number of adults with DM and ADM by a group of dermatologists, and it has been shown to be reliable and exhibit good construct validity in a small study. The CAT, DSSI and CDASI have undergone preliminary comparisons , but further research is needed to determine which of these tools will perform best in clinical and research contexts.
Cutaneous lesions in individuals with darker complexions (skin types III-VI) can appear quite different than the same lesions in patients with more fair complexions (skin types I-II) . The evaluation of cutaneous findings of IIM in patients skin types III-VI can present particular challenges. Erythema can be more difficult to detect in these patients, and hyperpigmentation can be mistaken for a patient's normal complexion or it can be thought to reflect inactive disease [102, 103]. For these reasons, care must be taken in the assessment of the IIM in patients with a range of skin types (see accompanying photo-essay).
Cutaneous involvement is important in IIM. In order to provide context for the accompanying photo-essay, this review has updated the current state of knowledge of skin disease in IIM, including associations with autoantibodies, malignancy-associated IIM, amyopathic variants of IIM, drug-induced IIM and lipodystrophy. In addition we have reviewed important advances in the understanding of pathogenesis, particularly as it pertains to the cutaneous involvement in DM. Finally, recent developments in the evaluation of skin disease in the IIM have been reviewed, hopefully leading to comprehensive and standardized assessments of skin disease in the IIM and better recognition of the spectrum of skin involvement in these rare, debilitating conditions.
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