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The Brazilian Society of Rheumatology recommendations on investigation and diagnosis of systemic autoimmune myopathies

Abstract

Background

This research is recommended by the Myopathy Committee of the Brazilian Society of Rheumatology for the investigation and diagnosis of systemic autoimmune myopathies.

Body

A systematic literature review was performed in the Embase, Medline (PubMed) and Cochrane databases, including studies published until October 2018. PRISMA was used for the review, and the articles were evaluated, based on the Oxford levels of evidence. Ten recommendations were developed addressing different aspects of systemic autoimmune myopathy investigation and diagnosis.

Conclusions

The European League Against Rheumatism/ American College of Rheumatology (EULAR/ACR) classification stands out for the diagnosis of systemic autoimmune myopathies. Muscular biopsy is essential, aided by muscular magnetic resonance images and electroneuromyography in complementary research. Analysis of the factors related to prognosis with the evaluation of extramuscular manifestations, and comorbidities and intense investigation regarding differential diagnoses are mandatory.

Background

Systemic autoimmune myopathies (SAM) are rare systemic muscle diseases that include dermatomyositis (DM), juvenile dermatomyositis, clinically amyopathic dermatomyositis, polymyositis (PM), juvenile myositis, antisynthetase syndrome, inclusion body myositis, immune-mediated necrotizing myopathies, overlapped myositis syndrome, cancer-associated myopathies, and among others [1, 2].

Among the several diagnostic criteria proposed, convergence was observed in the evaluation of the following aspects: muscle weakness, observation of inflammatory infiltrate in muscle biopsy, electroneuromyography evaluation, serum muscle enzymes with special emphasis on creatine phosphokinase (CPK), and specific myositis antibodies. Comorbidities should be investigated, highlighting the presence of neoplasia, and a thorough investigation must always be carried out with regard to differential diagnoses [3, 4].

The purpose of these recommendations is to guide the investigation and diagnosis of SAM patients according to the current evidence in the literature.

Methods

A systematic literature review was performed in the following databases: Embase, Medline (PubMed), and Cochrane. The analysis was performed according to each “PICO” question (Patient, Intervention, Control, Outcome).

The following English terms were used in the systematic review of the literature: Autoimmune OR Autoimmune Disease OR Autoimmune Diseases OR Systemic OR Polymyositis OR Idiopathic Polymyositis OR Idiopathic OR Dermatomyositis OR Dermatopolymyositis OR Dermatopolymyositis OR Myositis OR Inflammatory Muscle Diseases OR Inflammatory Myopathy OR Inflammatory Myopathies) AND (Muscular Disease OR Myopathies OR Muscle Disorders OR Muscle Disorders OR Myopathic Conditions OR Myopathic Conditions.

With the application of a random filter, the terms related to each modality of investigation and diagnoses for SAM were included.

The inclusion criteria for the present study were: randomized and controlled trials (RCT) addressing SAM diagnosis and investigation, extension studies derived from RCTs with the criteria mentioned above and systematic reviews with RCT meta-analysis. In some cases, review articles and historical cohort studies were included and, in the absence of RCTs for specific modalities of therapy, open studies or low-quality cohort studies were accepted.

The steps in this systematic review followed the PRISMA guidelines [5]. The selected studies were evaluated, and the quality of the evidence and level of agreement for each question was based on the level of evidence from the studies (Tables 1 and 2) [6,7,8]. Ten recommendations were developed addressing different aspects of SAM investigation and diagnosis.

Table 1 Categories of evidence in studies
Table 2 Quality of evidence

Recommendations

What are the classification criteria for SAM?

From 3297 records identified through database searching, 10 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

A series of diagnostic criteria for SAM was developed by Bohan and Peter, Dalakas, Tanimoto, Targoff and the European Neuromuscular Center (ENMC). The classification of Dalakas, with a sensitivity of 77.1% and a specificity of 99.0%, showed better performance, followed by the ENMC criterion, with a sensitivity of 71.4% and a specificity of 82.4% (B) [9,10,11,12,13,14].

Medical records of adults diagnosed with DM according to the classification of Bohan and Peter were submitted to the European League Against Rheumatism / American College of Rheumatology (EULAR / ACR) criteria due to the inclusion of cutaneous rash (heliotrope rash and Gottron’s sign or papules) [15]. DM cutaneous findings were measured by activity using the Severity Index and cutaneous dermatomyositis disease area (CDASI) to show which variables presented more frequently in patients with active DM including classic, amyopathic and hypomyopathic forms (C) [15].

The evaluation of the performance of EULAR / ACR in patients for whom a muscle biopsy was performed resulted in a sensitivity of 93% and specificity of 88%; disregarding the histological criterion indicated a sensitivity of 87% and a specificity of 82% (B) [2, 16]. Of note, the EULAR / ACR classification criteria [2] excluded the necessity of the electroneuromyography exam and aldolase serum dosing.

Similarly, all analyzed criteria showed the relevance of muscle biopsy, whose main objective is to rule out other possible causes of myopathies, in addition to helping to characterize the type of SAM. Biopsy is an important complementary exam in suspected cases of myopathies, especially in patients without characteristic skin involvement.

Overall, among the criteria, those of EULAR / ACR and ENMC performed better in the comparisons evaluated.

Recommendations

SAM classification criteria may help with diagnoses, provided other myopathies have been ruled out. Specifically, the EULAR / ACR criteria deserve special mention, mainly when associated with muscle biopsy (quality of evidence B; level of agreement > 90%).

When should muscle biopsy be indicated in patients with SAM?

From 9275 records identified through database searching, 14 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

In defined DM, perifascicular, perimysial or perivascular infiltrate and perifascicular atrophy are present (D) [17]. In immune-mediated necrotizing myopathy, the biopsy predominantly shows necrotic muscle fibers, sparse inflammatory cells in the perivascular space, and infiltrate of the perimysium (D) [12].

In PM, muscle biopsy shows cytotoxic CD8+ T lymphocyte endomysial inflammatory infiltrate, in necrotic and nonnecrotic fibers expressing major histocompatibility complex (MHC)-I [18,19,20,21,22].

Due to the presence of inflammatory infiltrate and mononuclear cells in muscle biopsy, the diagnostic utility of MHC-I has been studied to differentiate in SAMs from other muscular diseases and may show interference by variations, for example, in antibody type and staining (B) [18,19,20,21,22].

When comparing the histology of PM and DM with muscle biopsies of patients with muscular dystrophy, it was observed that MHC-I was regulated along the membrane of muscle fibers in patients with SAM, which helps in the differentiation from neuromuscular diseases (B) [18, 23, 24].

Therefore, when possible, rheumatologists should obtain muscle biopsy samples from all patients unless they present with unequivocal DM skin lesions (B) [24]. Moreover, immunohistochemistry (i.e., MHC staining) should b also be included in routine muscle biopsy panel analysis whenever possible.

As mentioned in the previous recommendation, all criteria include muscle biopsy to better characterize SAM and to exclude myopathies from another origin.

Recommendations

Muscle biopsy in patients with SAM may aid in the diagnosis of their subtypes and differentiate this disease from noninflammatory myopathies. MHC labeling mainly contributes to differentiating SAM from muscular dystrophies (quality of evidence B, level of agreement > 90%).

When should magnetic resonance imaging of muscles be indicated in patients with SAM?

From 428 records identified through database searching, 5 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

Analysis of the distribution and extension of muscle inflammation through full-body magnetic resonance imaging (MRI) in SAM patients and subsequent biopsy of the muscle guided by these findings are described as a potential aid in the diagnosis of these diseases (B) [25,26,27].

This technique allows for the early identification of oligosymptomatic myositis, accurately detecting the most severely affected muscle candidates for biopsy, providing a reliable baseline method to monitor disease progression and response to treatment (B) [25,26,27].

Although imaging diagnostic methods with MRI have not been included in the EULAR / ACR classification criteria [2], the ability to demonstrate possible patterns of tissue alteration shows the possibility of their use as a complementary method in differentiating acquired and hereditary myopathies.

Recommendations

Magnetic resonance images can be used as a guide to muscle biopsy, to identify oligosymptomatic myositis and possible kinds of myopathies, and to monitor disease progression and response to treatment (quality of evidence B, level of agreement > 90%).

When should electroneuromyography be indicated in patients with SAM?

From 2064 records identified through database searching, 14 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

Studies have demonstrated variable accuracy of electroneuromyography in different SAM, at similar rates in DM compared to PM (B) [28], and the evaluation of muscle fiber conduction velocity did not help to discriminate SAM from other myopathies (B) [29, 30].

In European centers, patients with myopathies of different etiologies, and even those with unknown etiologies were evaluated using three different diagnostic consensuses: clinical, electrodiagnostic and final consensus (clinical evaluations and electroneuromyography results). High sensitivity (90.2%) of electroneuromyography was observed in SAM [31,32,33]. Nevertheless, due to its low specificity, electroneuromyography has been withdrawn from the new EULAR / ACR 2017 [2].

Complementary tests before and after 6 months and 12 months of treatment indicated that increased muscle strength and decreased serum enzyme levels were associated with decreased spontaneous activity and the proportion of high-frequency components in electroneuromyography, except during the initial treatment period, when a temporary increase of high-frequency components was recorded (C) [34].

It was also shown that fiber density was slightly higher in the normal or neurogenic subgroup than in the myogenic subgroup, but without statistical significance (C) [35]. Finally, motor unit potentials and a myopathic interference pattern were present in equal numbers in treated and nontreated DM patients (B) [36]. Therefore, electroneuromyography may have an additional role in the diagnosis of SAM but plays no role in its follow-up (B) [36]. The exam is also important to distinguish eventual muscular weakness secondary to neurogenic affection.

Recommendations

Electroneuromyography in the diagnostic investigation can identify patients with myopathies, but it plays no role in the follow-up (quality of evidence B; level of agreement > 90%).

What are the myositis-specific or myositis-related antibodies that can assist in the diagnosis and/or follow-up of SAM patients in daily practice?

From 2974 records identified through database searching, 36 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

Among the several antibodies identified, we present some antibodies that stand out in SAM.

Eight anti-aminoacyl-tRNA synthetase autoantibodies are described (A) [37]. The most prevalent is anti-Jo-1 (histidyl-tRNA synthetase), which can be identified in more than 20% of adult patients with a diagnosis of SAM (B) [38, 39] (C) [40], and due to its importance, this was included in the new EULAR / ACR 2017 SAM classification criteria [2]. Anti-Jo-1 is usually associated with manifestations that constitute the antisynthetase syndrome characterized by interstitial lung disease (ILD), Raynaud’s phenomenon, arthritis and hyperkeratosis of the lateral part of the fingers and palms, a condition known as “mechanic hands.” This antibody can also be found in cases of typical antisynthetase syndrome skin rashes. Other antisynthetase autoantibodies such as anti-PL-17 (threonyl-tRNA), anti-PL-12 (alanyl-tRNA), anti-EJ (glycyl-tRNA), anti-Ha (tyrosyl-tRNA), anti-OJ (isoleucyl-tRNA), anti-Zo (phenylalanyl-tRNA) and anti-KS (asparagil-tRNA) are less commonly found in this clinical condition [37,38,39,40].

In addition, evidence suggests that some aspects of the disease could vary depending on which antibody is present. Muscle disease, for example, is most frequently present among patients positive for anti-Jo-1, anti-PL-7, and anti-EJ (B) [41]. Arthritis is most associated with anti-Jo-1 and anti-PL-7; on the other hand, positivity of anti-KS, anti-OJ and anti-PL-12 is more associated with ILD (B) [37,38,39,40,41,42]. In addition, other myositis-specific and myositis-associated autoantibodies may be present, such as anti-melanoma differentiation-associated protein 5 (anti-MDA-5) and anti-PM/Scl, respectively (B) [43]. The presence of anti-MDA-5 is associated with rapidly progressive ILD (A) [44]. It has been used as a marker of response to treatment (B) [43, 45] (C) [46] and of poor prognosis; more than 40% of anti-MDA-5 positive patients die of respiratory failure (B) [47]. On the other hand, patients with anti-Jo-1 autoantibodies have better survival rates (B) [48].

Immune-mediated necrotizing myopathy is an SAM subtype associated with rapid development of muscle weakness and the presence of anti-signal recognition particle (anti-SRP), a specific myositis autoantibody that occurs in the context of acute onset of the disease, with severe myopathy and aggressive disease (C) [49, 50]. Dysphagia and ILD are also found in anti-SRP-positive patients (B) [51]. Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) is also associated with this myositis subtype, especially in patients with a previous history of statin use (B) [52] (D) [53]. An observational study designed to evaluate the severity of the disease and response to therapy in patients with myositis associated with the anti-HMGCR autoantibody found that young individuals had a more severe disease and a worse prognosis compared to older individuals (B) [54].

Anti-Mi-2 (directed against the nucleosome deacetylase complex) is associated with the phenotype of cutaneous signs (“shawl” sign, heliotrope rash and photosensitivity), clinically significant weakness, and high levels of muscle enzymes. The prognosis of patients with anti-Mi-2 is a good response to glucocorticoid treatment and a decreased risk of neoplasia and pulmonary disease (B) [55].

Myositis-specific autoantibodies related to a higher risk of malignancy in SAM patients include anti-transcriptional intermediary factors (TIF)-γ and anti-nuclear matrix protein (NXP)-2 (B) [56,57,58].

Anti-Ku, anti-PM/Scl and anti-nuclear ribonucleoprotein (anti-RNP) antibodies are generally identified in patients with overlapping manifestations of myositis and other autoimmune systemic diseases such as scleroderma, systemic lupus erythematosus and mixed connective tissue disease [59]. These individuals are probably the largest subgroup of patients who are diagnosed with SAM, with a prevalence of up to 50% of all adult individuals (D) [59]. Although these manifestations are nonspecific, they may correlate with some clinical characteristics of SAM (B) [60, 61].

Anti-PM / Scl is most commonly found in the association of systemic sclerosis, conferring an increased risk of interstitial lung disease, arthritis, mechanic’s hands and Raynaud’s phenomenon, increased CPK, constitutional disease activity, severity of dysphagia, and poor prognosis [61]. Anti-Ku was originally found in a variety of connective tissue disease conditions, being associated with higher rates of arthralgia, Raynaud’s phenomenon, musculoskeletal manifestations, and a high frequency of interstitial lung disease [60]. Finally, patients with anti-U1-RNP rarely have myositis at initial presentation and respond favorably to glucocorticoid treatment, suggesting that this is a marker of good prognosis [59].

Myositis-specific autoantibodies are not essential to the treatment but are useful in some cases, especially when it is not possible to obtain a definitive diagnosis with muscle biopsy, being useful to accrue prognostic information and evaluate associated manifestations (B) [60, 61].

Recommendations

Autoantibodies can be found in patients diagnosed with SAM. They are not essential to the treatment but are useful in doubtful cases to accrue prognostic information and associated manifestations (quality of evidence B; level of agreement > 90%).

In the initial and late phases, which types of cancers should be searched for SAM? How often should the screening be done?

From 36,547 records identified through database searching, 18 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

Individuals with DM present a higher risk of malignancy compared to those diagnosed with PM (overall relative risk of 4.6 and 1.7, respectively) (A) [62], Although increased incidence of cancer in these patients can partially be attributed to the investigations requested for these individuals, particularly during the first year after diagnosis in tertiary centers (B) [63], evidence has pointed to a real higher incidence even before the diagnosis is established, thus suggesting a true association between the diagnosis of SAM and cancer (A) [64]. Despite the recognition of this association, the types of cancer remain somewhat controversial, including a broad spectrum of malignancies such as breast, lung colorectal, nasopharynx, body of the uterus, and gastric cancer, which are significantly influenced by gender and ethnicity [62,63,64,65,66,67,68,69].

In particular, a multicenter study of patients with DM found a significantly elevated risk for lung, ovarian, pancreatic, gastric, and colorectal cancer and non-Hodgkin’s lymphoma [69]. In patients with PM, an increased risk of non-Hodgkin’s lymphoma and lung and bladder cancer was observed (B) [70]. The most common type of cancer was adenocarcinoma, accounting for 70% of all tumors associated with both diseases (B) [70].

There is a higher risk of neoplasms occurring among older individuals (B) [71, 72]. The evaluation should include prostate and testicular examination in men, breast and pelvic examination in women and rectal examination in all patients. Women with a recent SAM diagnosis should be extensively examined and submitted to mammography and pelvic ultrasonography [71, 72]. Some neoplasms may not yet be identified in a screening program such as lymphoma, ovarian, pancreatic, or lung cancer [71, 72]. Thus, computed tomography examination of the thorax, abdomen, and pelvis may be considered in a subgroup of patients with SAM who have risk factors for specific types of neoplasia, such as a positive family history of ovarian or breast cancer [71, 72]. Gastrointestinal endoscopy and colonoscopy should be utilized on a case-by-case basis [71, 72].

Studies show a lack of uniformity in the definition of the temporal association between neoplasia and the diagnosis of SAM [62,63,64,65,66,67,68,69,70,71,72]. Thus, there has been no consensus until recently regarding how and when this screening should be conducted.

Recommendations

There is no concise information about the screening of neoplasms, and no consensus, regarding how and when this screening should be conducted. However, in our opinion, adults with this diagnosis, highlighting DM, should be screened, requesting specific tests mainly according to gender, age, ethnicity, and familiar history (quality of evidence B; level of agreement > 90%).

Which comorbidities should be (re) evaluated regularly in patients with SAM?

From 36,547 records identified through database searching, 22 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

Virtually all individuals with conditions associated with muscle weakness, such as those found in SAM, are susceptible to the development of low bone mass density (B) [73,74,75] (A) [76, 77]. Moreover, these individuals are exposed to an additional risk factor since glucocorticoids represent the first-line treatment (B) [78] (D) [79, 80]. Individuals who face significant deterioration of bone mass density and/or bone microarchitecture impairment are at a high risk of fracture (A) [81], making it imperative to periodically investigate using the X-ray dual-density densitometry method (B) [82]. An observational study conducted with the objective of assessing the prevalence of osteoporosis and occurrence of fractures in adults with SAM identified that osteoporosis was more frequently diagnosed compared to controls with a high prevalence of fractures (B) [82].

Although rarely symptomatic, subclinical cardiac manifestations are usually identified in patients with myopathies, and their prevalence varies widely according to the way the patient is investigated (electrocardiogram, echocardiogram, Holter, cardiac MRI) [83, 84]. The most frequent abnormalities are cardiomyopathy, dilated cardiomyopathy, heart failure, myocarditis, pericarditis, conduction defects and arrhythmias (A) [83] (D) [84]. The occurrence of arterial microvascular disease associated with acute myocardial infarction has also been reported [84, 85]. Nevertheless, patients may demonstrate combinations of more than one type of heart involvement [84, 85]. Clinical evaluation, including detailed anamnesis and physical examination is of paramount importance at the time of diagnosis, and some tests are recommended, such as an electrocardiogram, to check for cardiac involvement with the presence of arrhythmias and conduction abnormalities (C) [85]. Other investigations such as echocardiography, myocardial scintigraphy, and MRI are indicated when clinically relevant at the time of diagnosis and during the follow-up period (C) [86].

The lung is the organ most frequently affected in SAM, which is also the main cause of death in this group of patients [84]. The main types of lung involvement are hypoventilation due to respiratory muscle weakness, interstitial pneumonia, and aspiration (D) [87] (B) [88]. Therefore, patients with myopathies should undergo pulmonary function evaluation at the time of diagnosis. Moreover, patients with a high risk of pulmonary function impairment and/or vital capacity reduction should be monitored more frequently (B) [88,89,90]. In these cases, assessment of noninvasive oxygenation of patients by oximetry may be indicated. The evaluation of pulmonary function may also include a 6-min walking test, respiratory video fluoroscopy and ergospirometry [88,89,90].

Dysphagia has been reported in 32–84% of SAM patients, and esophageal involvement assessed by high-resolution manometry is common in patients with SAM, but it correlates poorly with esophageal symptoms. Failed waves and decreased upper esophageal sphincter pressure are more common in PM than in DM patients (B) [91].

Recommendations

The management of patients with myopathies should consider care aimed at limiting the effects of muscle weakness, on joints, bones and other systems. In addition, comorbidities should be screened for and treated when necessary, optimizing the functional capacity and thereby improving quality of life of patients (quality of evidence B; level of agreement > 90%).

What are the main differential diagnoses of SAM?

From 36,547 records identified through database searching, 9 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

The identification of certain extramuscular manifestations may suggest the possibility of mitochondrial myopathy such as the presence of cognitive alterations, hearing and extraocular muscle impairment, convulsions, and neuropathy in patients with mitochondrial encephalomyopathy (D) [92]. Serum CK levels may be normal, and muscle biopsy stained by the Gomori trichrome revealed the presence of fibers with increased reddish granulation [92]. It should be noted, however, that although these findings are indicative of mitochondrial dysfunction, they may be identified in many other disorders and are not specific to the diagnosis of hereditary mitochondrial myopathy (D) [93].

Another important differential diagnosis is metabolic myopathies, characterized by defects in muscle tissue utilization of carbohydrates or fats, resulting in a decrease in energy supply [94, 95]. These myopathies manifest as cramp attacks and muscle weakness, often associated with myoglobinuria [94, 95]. Some metabolic myopathies, such as acid maltase deficiency (Pompe’s disease) and glycogen storage disease type V (McArdle’s disease) may manifest with episodic proximal muscle weakness [75, 94]. This pattern may eventually lead to confusion with the diagnosis of SAM, especially in the presence of a history of chronicity and nonidentification of myoglobinuria (C) [94, 95].

Endocrine myopathies should also be considered in the differential diagnosis [96]. Myopathy related to hypothyroidism is typically characterized by muscle discomfort associated with mild to moderate proximal muscle weakness [96]. Serum CK levels may be slightly elevated, and there appears to be no association between the degree of muscle weakness and the severity of hypothyroidism (B) [96]. Hyperthyroidism is also associated with myopathy, although it seems to be a less common occurrence than that observed in cases of hypothyroidism [96]. A study identified that approximately 60% of patients with untreated hyperthyroidism showed clinical evidence of proximal muscle weakness; however, only 10% had myopathic changes in electromyography (B) [95]. Hyperparathyroidism may occasionally cause proximal muscle weakness syndrome. Additionally, CK levels that are normal or slightly elevated with muscle biopsy may indicate atrophy without alteration in muscle fiber arrangement [96].

Drug-induced myopathies are also a differential diagnosis [97]. As a classic example, statins may be associated with varying forms of muscle symptoms and toxicity, such as myalgia (1 to 10%), myositis (defined by muscle symptoms and increased CK levels), and rhabdomyolysis (increases in CK with evidence of injury) (D), most commonly observed in patients with hypothyroidism, in those who are using multiple drugs, and even in those who abuse alcoholic beverages (D) [97].

Some infections may cause chronic myopathy that may resemble PM [98]. These infections are often triggered by acute viral illness, such as the Coxsackie or influenza virus [98]. Human immunodeficiency virus may also be associated with muscle weakness, either as a characteristic of the infection itself or in later stages of the disease [98]. In addition to myopathic changes, there may be evidence of axonal sensory neuropathy [98]. Bacterial infections, except for Lyme disease and syphilis, may present with focal pyomyositis (D) [98].

Finally, muscular dystrophies should also be considered as differential diagnoses, mainly in PM or PM-like conditions, since these conditions may mimic the clinical manifestations of SAM. Some features may suggest the diagnosis of muscular dystrophies, such sa positive family history, prolonged course of muscle weakness, facial weakness, abnormalities of eye movement, distal weakness equal to or greater than proximal weakness, and asymmetrical weakness.

Recommendations

Several conditions may mimic the clinical manifestations of SAM. Moreover, the absence of specific autoantibodies and systemic features related to autoimmunity and refractoriness to immunosuppressive drugs should also raise the suspicion of alternative diagnoses (quality of evidence B; level of agreement > 90%).

Which clinical / laboratory findings result in poor response to drug treatment in SAM?

From 9275 records identified through database searching, 14 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

The International Myositis Assessment & Clinical Studies Group (IMACS) suggested, regarding the status of the disease, some measures as a global evaluation of the disease activity perceived by the patient and physician. Muscle strength assessed by Muscle Manual Testing (MMT); functional capacity measured by the Health Assessment Questionnaire (HAQ); elevated serum levels of at least two muscle enzymes (CK, aldolase, lactate dehydrogenase, aspartate and alanine aminotransferases); and extramuscular manifestations of the disease assessed by the Myositis Disease Activity Assessment Tool (MDAAT) may be used for the purpose of monitoring disease activity and as indicative of poor response to treatment (D) [99]. However, in addition to few measures being fully validated, it is still difficult to differentiate disease activity from accrual damage [99].

Despite the relationship with ILD, antisynthetase antibody positivity is a predictor of clinical response to rituximab in individuals with refractory myositis (B) [100,101,102]. Reports indicate that patients with ILD-positive anti-OJ present a good prognosis as well as a positive response to glucocorticoid therapy (C) [103]. Anti-exosome (anti-PM/Scl) presence does not appear to be a good prognostic factor and is associated with pulmonary and esophageal involvement (C) [104].

Recommendations

Cytokines and specific or related myositis antibodies aiming to discriminate the disease activity and to predict the prognosis of the treatment. However, it is important to note that the available evidence on the use of laboratory findings for this purpose shows variable results in terms of performance, lacking a standardized approach (quality of evidence B; level of agreement > 90%).

The available evidence on the use of laboratory tests or other standardized tools to evaluate disease activity and/or to predict the response to treatment shows variable results in terms of performance, lacking a standardized approach. At this point, we recommend the use of laboratory markers, such as CPK, and tools, such as physician and patient global evaluation of the disease activity as guides to disease activity, and treatment response (quality of evidence B; level of agreement > 90%).

Which organs and/or systems should be routinely reevaluated in patients with SAM?

From 36,892 records identified through database searching, 20 studies were selected to answer the present question (Additional file 1).

Literature review and analysis

In addition to the considerable heterogeneity in the presentation and prognosis of the SAM, extramuscular involvement is often observed. There may be concurrent involvement of cardiovascular, respiratory, digestive, kidney, endocrine, ocular, dermatological, hematological, and nervous systems (B) [83, 87, 105,106,107,108,109]. The extent and severity of systemic organ involvement also vary substantially in each SAM category (DM, PM, immune-mediated necrotizing myopathy) [83, 87, 105,106,107,108,109].

SAM patients present survival rates estimated between approximately 60 and 70%, with deaths mainly related to cardiac and pulmonary involvement, as well as the occurrence of cancers and infections affecting the respiratory and gastrointestinal tract (B) [88, 110]. The cause of death in individuals depends on the duration of the disease. Death related to pulmonary complications usually occurs in the first year of disease, while cardiovascular complications are the most common cause of death 5 years after diagnosis (B) [111]. Therefore, all individuals should be referred for cardiac and lung function assessment at the time of diagnosis of SAM, and clinical evaluation, including detailed anamnesis and physical examination is essential [108]. Some tests are recommended, such as electrocardiogram and the evaluation of pulmonary function, to verify cardiac involvement with arrhythmias and conduction abnormalities and impairment of pulmonary function as a reduction in vital capacity (B) [90, 112] (C) [85] (D) [113].

Gastrointestinal disorders compromise the oropharynx, esophagus, stomach, liver, small intestine, colon, and rectum, and there is a substantial increase in the risk of occult malignancies, including gastrointestinal cancers, mainly observed in the first year after diagnosis (B) [70, 114, 115]. Thus, extensive anamnesis and physical examination are mandatory in newly diagnosed patients, and a high suspicion of underlying malignancy should be maintained. High-risk characteristics for malignancy include advanced age, myopathy refractory to glucocorticoid treatment, presence of severe cutaneous rash, and being negative for some autoantibodies [anti-histidyl tRNA synthetase (Jo-1), anti-PM/Scl, anti-U1-RNP, anti-U3-RNP and anti-Ku antigen] [116, 117], requiring a more complete evaluation in regard to cancer screening and surveillance.

Recommendations

The manifestation of SAM is heterogeneous. Therefore, cardiovascular, respiratory and gastrointestinal evaluations should be performed when indicated. Care should also be taken to ensure a neoplasm screening and surveillance program (quality of evidence B; level of agreement > 90%).

Conclusions

Among all criteria, the EULAR / ACR 2017 stands out for the diagnosis of SAM. Muscular biopsy is essential, aided by muscular magnetic resonance images and electroneuromyography in complementary research. Analysis of factors related to prognosis with evaluation of extramuscular manifestations, and comorbidities and intense investigation regarding differential diagnoses are mandatory.

Availability of data and materials

Not applicable

Abbreviations

ACR:

American College of Rheumatology

CDASI:

Cutaneous dermatomyositis disease area

CPK:

Creatine phosphokinase

DM:

Dermatomyositis

ENMC:

European Neuromuscular Center

EULAR:

European League Against Rheumatism

HAQ:

Health Assessment Questionnaire

HMGCR:

3-hydroxy-3-methylglutaryl-coenzyme A reductase

IL:

Interleukin

ILD:

Interstitial lung disease

IMACS:

International Myositis Assessment and Clinical Studies Group

IP:

Interferon gamma-induced protein

MDA:

Melanoma differentiation-associated gene

MDAAT:

Myositis Disease Activity Assessment Tool

MMT:

Muscle Testing Manual

MRI:

Magnetic resonance imaging

NXP:

Nuclear Matrix Protein

PICO:

Patient, Intervention, Control, Outcome

PM:

Polymyositis

RCT:

Randomized controlled trials

RNP:

Nuclear ribonucleoprotein

SAM:

Systemic autoimmune myopathies

SDF:

Stromal cell-derived factor

SRP:

Signal recognition particle

TIF:

Transcriptional intermediary factor

TNF:

Tumor necrosis factor

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Acknowledgments

Renata Miossi, and Mailze Campos Bezerra who contributed to the elaboration of questions.

Funding

Brazilian Society of Rheumatology.

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FHCS contributed to the elaboration of questions. He was a major contributor in writing and reviewing the manuscript. DBA contributed to the elaboration of questions and the manuscript revision. VSS contributed to the elaboration of question and the manuscript revision. RSS contributed to systematic literature review. WMB contributed to systematic literature review. TAF contributed to systematic literature review. BMC contributed to the elaboration of questions and the manuscript revision. SKS contributed to the manuscript organization, elaboration of questions and manuscript revision. All authors read and approved the final manuscript.

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Correspondence to Samuel Katsuyuki Shinjo.

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Supplementary information

Additional file 1.

The studies selection process during the systematic review. (DOCX 23 kb)

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de Souza, F.H.C., de Araújo, D.B., Vilela, V.S. et al. The Brazilian Society of Rheumatology recommendations on investigation and diagnosis of systemic autoimmune myopathies. Adv Rheumatol 59, 42 (2019). https://doi.org/10.1186/s42358-019-0085-5

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Keywords

  • Autoantibodies
  • Electroneuromyography
  • Magnetic resonance
  • Muscle biopsy
  • Systemic autoimmune myopathies