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Autoantibody testing in idiopathic inflammatory myopathies
  1. Anke Rietveld1,
  2. Johan Lim2,
  3. Marianne de Visser2,
  4. Baziel van Engelen1,
  5. Ger Pruijn3,
  6. Olivier Benveniste4,
  7. Anneke van der Kooi2,
  8. Christiaan Saris1
  1. 1 Department of Neurology, Center for Neuroscience Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2 Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
  3. 3 Department of Biomolecular Chemistry, Radboud Institute for Molecular Life Sciences and Institute for Molecules and Materials, Nijmegen, The Netherlands
  4. 4 Médecine Interne et Immunologie Clinique, Centre de Référence Maladies Neuro-Musculaires, Sorbonne Université, AP-HP, GH Pitié-Salpêtrière, UMR974, Paris, France
  1. Correspondence to Dr Anke Rietveld, Department of Neurology, Center for Neuroscience Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands; Anke.Rietveld{at}radboudumc.nl

Abstract

The diagnosis and classification of idiopathic inflammatory myopathies are based mainly on clinical and histological features. The discovery of myositis-specific and myositis-associated antibodies has simplified the (sub)classification of inflammatory myopathies. Patients suspected of having an idiopathic inflammatory myopathy should undergo routine antibody testing to gain more insight into distinct phenotypes, comorbidities, treatment response and prognosis. Furthermore, autoantibody testing can help in patients with atypical patterns of weakness or with an unresolved limb-girdle myopathic phenotype, or interstitial lung disease. However, some important technical and methodological issues can hamper the interpretation of antibody testing; for example, some antibodies are not included in the widely available line blots. We aim to provide a practical review of the use of autoantibody testing in idiopathic inflammatory myopathies in clinical practice.

  • incl body myositis
  • polymyositis
  • neuroimmunology
  • neuromuscular

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Background

The classification of idiopathic inflammatory myopathies in adults is based mainly on the clinical phenotype and histopathological features of muscle biopsies. In recent decades, the number of subtypes of idiopathic inflammatory myopathies has expanded rapidly with the discovery of over 30 different myositis-associated and myositis-specific autoantibodies. Myositis-specific antibodies occur only with distinct subtypes of myositis, whereas myositis-associated antibodies occur in myositis, not limited to distinct subtypes, and in other connective tissue disorders. Autoantibody testing, which is non-invasive and rapid, could refine the diagnosis of myositis subtype, allowing for tailored treatment and individualised prognosis, and improved stratification in drug trials.

With the growing availability of autoantibody screening methods, it is important that physicians should know how to interpret the laboratory results.

Idiopathic inflammatory myopathies

Classification

In this overview, we use a very comprehensive—yet partially validated—classification of idiopathic inflammatory myopathies involving five groups1 :

  • Dermatomyositis.

  • Antisynthetase and related syndromes.

  • Non-specific (‘overlap’) myositis.

  • Immune-mediated necrotising myopathy (also called necrotising autoimmune myopathy).

  • Inclusion body myositis.

Antisynthetase syndrome is defined as a combination of myositis, skin changes (‘mechanic’s hands’), arthritis, Raynaud’s phenomenon and interstitial lung disease in the presence of one of the eight known anti-aminoacyl transfer RNA synthetase antibodies.

Approach to investigation

The diagnosis of idiopathic inflammatory myopathy is based on a set of criteria combining clinical, laboratory and histopathological findings.2–5 Each criterion has a different level of diagnostic certainty. New diagnostic criteria are being developed taking account of improved knowledge of autoantibodies and of imaging modalities. In clinical practice, a patient suspected of having an idiopathic inflammatory myopathy should undergo laboratory testing (serum creatine kinase activity, muscle-specific/muscle-associated autoantibodies) and muscle biopsy, if possible guided by muscle ultrasound scan or (whole body) MR imaging. Muscle biopsy is still of utmost importance in patients suspected of idiopathic inflammatory myopathy, as some congenital, dystrophic, toxic or metabolic myopathies can mimic this condition and because its current classification is still largely based on histopathological features. We can sometimes avoid performing a muscle biopsy, for example in patients with suspected dermatomyositis who have classical skin lesions and the presence of myositis-specific autoantibodies.

Table 1 lists the autoantibodies associated with idiopathic inflammatory myopathies.

  • The myositis-specific autoantibodies associated with dermatomyositis are anti-TIF1-γ, anti-MDA5, anti-SAE1, anti-Mi2 and anti-NXP2. The frequency of each of these varies greatly between different cohorts.

  • The eight known anti-tRNA synthetase antibodies are anti-Jo1, anti-PL7, anti-PL12, anti-OJ, anti-KS, anti-ZO, anti-EJ and antityrosyl-tRNA synthetase, with anti-Jo1 being the most prevalent (9%–30%), followed by anti-PL7 and anti-PL12 (3%–4%).6 7

  • The non-specific myositis-associated antibodies are anti-PM-Scl, anti-RNP, anti-Ku, anti-SSA (Ro52 and Ro60) and anti-SSB (La).

  • The only antibody associated with inclusion body myositis is anti-cN-1A, occurring in about one-third of patients.8

  • About half of children with myositis have autoantibodies: anti-TIF1-γ and anti-NXP2 occur most frequently, followed by MDA5 in certain cohorts (very common in Asia).9

Table 1

Classical clinical features of idiopathic inflammatory myopathies

Finding an autoantibody in a patient with suspected idiopathic inflammatory myopathy may support the diagnosis. Furthermore, the antibody status may relate to associated comorbidity, which determines tailored follow-up as explained below. Detecting autoantibodies can also help in patients where there is diagnostic doubt, such as in unexplained severe acute interstitial lung disease related to anti-MDA5 positivity, or in cases of isolated skin lesions without muscle weakness, the so-called amyopathic dermatomyositis. Furthermore, autoantibodies can help to assess patients with limb-girdle weakness without a molecular diagnosis, which could be caused by slowly progressive anti-SRP or anti-HMGCR immune-mediated necrotising myopathy.

Clinical features

The main clinical features of idiopathic inflammatory myopathies are the subacute onset (within 9 months) of progressive symmetrical proximal muscle weakness and a generally favourable response to immunosuppressive treatment. The exception is immune-mediated necrotising myopathy, which is notoriously difficult to treat.4 Inclusion body myositis, although traditionally classified as an idiopathic inflammatory myopathy, is the odd one out; it is characterised by slowly progressive and often asymmetric weakness, with no response to immunosuppressive treatment. The serum creatine kinase activity may be very high in antisynthetase syndrome and in immune-mediated necrotising myopathy, but may be normal in dermatomyositis and inclusion body myositis. Idiopathic inflammatory myopathies may also show extramuscular features; indeed, some variants of dermatomyositis and antisynthetase syndrome have little or no muscle involvement.2 Also some patients do not have the canonical features from the onset, such as the skin lesions in dermatomyositis, which may hamper an accurate diagnosis.

Table 1 summarises the typical clinical features of the idiopathic inflammatory myopathies and the association between autoantibodies and certain clinical features and comorbidities.

Muscle involvement

Subacute-onset symmetric proximal weakness is the main characteristic of most idiopathic inflammatory myopathies, with some exceptions. There are clinically amyopathic forms of dermatomyositis and antisynthetase syndrome: for example, anti-MDA5-positive patients (and some with antisynthetase syndrome) may have severe interstitial lung disease with little or no muscle involvement. Patients with immune-mediated necrotising myopathy may show rapid progression of weakness with very high serum creatine kinase activity, but occasional patients have slow progression mimicking limb-girdle muscle dystrophy.6 Conversely, some patients with limb-girdle dystrophies are misdiagnosed as having idiopathic inflammatory myopathy due to the combination of proximal weakness, high serum creatine kinase and inflammatory changes in the muscle biopsy. In those cases, careful clinical examination mostly shows a pattern that differs from idiopathic inflammatory myopathy (facial, scapular or distal muscle involvement).10 However, patients with idiopathic inflammatory myopathy can have extensive atrophy in the shoulder region; the slowly progressive weakness of the proximal, distal, axial and facial muscles, especially in inclusion body myositis, could mislead the clinician (figure 1).

Figure 1

Bilateral finger flexor weakness in a patient with inclusion body myositis, attempting to make a fist.

Cancer-associated myositis

Case 1: paraneoplastic syndrome

A 77-year-old man with a history of gout and type 2 diabetes mellitus was referred to dermatology for evaluation of a rash on the face, scalp and neck. Examination showed extensive heliotrope erythema and Gottron’s papules, consistent with classic dermatomyositis. One month after the rash appeared, he was—after the work-up for anaemia—diagnosed with metastasised prostate carcinoma. Over the next few months the rash extended to the rest of the body, despite cancer treatment and topical corticosteroids, and he developed muscle weakness. The prostate cancer was in complete remission after chemotherapy and hormone therapy. When assessed in the department of neurology, he had fatigue, weight loss and shortness of breath and proximal weakness. Examination showed weakness of the neck flexors and proximal limbs. Ancillary investigations showed minimally elevated serum creatine kinase (1.2× the upper limit of normal) and anti-TIF1-γ autoantibodies. He was subsequently treated with corticosteroids and methotrexate; we added intravenous immunoglobulins because of persisting disease activity. To date, his myositis disease activity is diminishing and there has been no cancer relapse.

This case illustrates that muscle biopsy can be omitted in specific circumstances (classic dermatomyositis skin changes and anti-TIF1-γ autoantibodies) and that myositis disease activity may persist irrespective of the remission of cancer.

Cancer-associated myositis is generally defined as the development of cancer in the 3 years before or after the diagnosis of idiopathic inflammatory myopathy. Dermatomyositis in adults is considered a classical paraneoplastic syndrome. Around 60%–80% of anti-TIF1-γ and 24%–38% of anti-NXP2-positive patients have cancer-associated myositis.11 The other dermatomyositis-associated autoantibodies apparently carry no increased risk of cancer, but there are few case series of patients older than 50 years (the risk of cancer increases with age). Patients with immune-mediated necrotising myopathy who are either seronegative or have anti-HMGCR antibodies have a higher incidence of cancer.12 Inclusion body myositis is not associated with cancer, and children with idiopathic inflammatory myopathies have no increased cancer risk.

There are also ethnic differences. Patients from European or American cohorts with antisynthetase syndrome have no increased risk of cancer, whereas a recent Asian study found an increased risk of cancer in anti-Jo1-positive and anti-PL12-positive patients.13 Additionally, this Asian cohort showed an increased cancer risk in patients with anti-SAE1-positive dermatomyositis, and in autoantibody-negative dermatomyositis, polymyositis and immune-mediated necrotising myopathy.

Adult patients with dermatomyositis or immune-mediated necrotising myopathy require extensive cancer screening, especially if aged over 50 years and in those who have lost weight, but also in those with anti-TIF1-γ, anti-NXP2 or anti-HMGCR antibodies and those with immune-mediated necrotising myopathy without antibodies. There are no large studies comparing cancer screening methods. Practice guidelines for dermatomyositis recommend CT scan of the thorax/abdomen, colonoscopy (for those aged over 50 years), pelvic ultrasound scan and mammography (for women), and ultrasound of the testes (for men younger than 50 years).14 15 These tests seem to be equivalent to fluorodeoxyglucose positron emission tomography-CT.15 The symptoms of idiopathic inflammatory myopathy can precede the appearance of the associated malignancy by a few years, justifying annual screening for 3 years after diagnosing idiopathic inflammatory myopathy in patients with a high-risk profile.14 15 There is no association between certain types of cancer and certain autoantibodies. The co-occurrence of cancer and idiopathic inflammatory myopathy may influence the prognosis: muscle symptoms might improve as the cancer is treated, although occasional patients do not improve despite cancer treatment.15 We still do not know the exact pathophysiological relationship between autoantibody development and cancer.

Pulmonary and respiratory comorbidity

Case 2: unexplained lung disease

A 62-year-old woman of Asian ancestry with a history of endometriosis and breast carcinoma (treated with surgery and radiotherapy 25 years earlier) reported a 1-month history of progressive dyspnoea and was diagnosed as interstitial lung disease of unknown cause (figure 2). She also had ulcerating skin lesions, ‘mechanic’s hands’, fever and weight loss. The differential diagnosis included a connective tissue disease-associated interstitial lung disease and acute interstitial pulmonary fibrosis, for which she was being treated with pulsed methylprednisolone and maintenance corticosteroid. Laboratory results showed an elevated serum C reactive protein of 35 mg/L (reference 0–5) and erythrocyte sedimentation rate of 70 mm/hour (reference 0–20). Serum creatine kinase activity, extensive investigations for infectious diseases, ACE, antineutrophil cytoplasmic antibody and antinuclear antibodies were normal. A relapse of breast cancer was excluded. The myositis line blot showed high titres of anti-MDA5 autoantibodies, leading to a diagnosis of interstitial lung disease in the setting of an amyopathic dermatomyositis. The lung disease was quickly progressive and did not respond to combined treatment with corticosteroids, cyclophosphamide and intravenous immunoglobulins, and she died.

Figure 2

CT scan of the thorax with intravenous contrast showing extensive bronchiectasis and subpleural cysts.

This case shows the diagnostic and prognostic value of autoantibody testing in unexplained lung disease.

The pulmonary and respiratory complications encountered in patients with idiopathic inflammatory myopathies are interstitial lung disease—sometimes complicated by pulmonary hypertension—and respiratory insufficiency due to muscle weakness. In addition, pulmonary infections occur more often in patients with bulbar weakness and dysphagia (see below) or as a complication of immunosuppressive treatment.

Anti-MDA5 is associated with severe, rapidly progressive and life-threatening interstitial lung disease. It can be the first symptom of the disease and may need managing by intensive care. Therefore, clinicians should consider testing for myositis autoantibody in patients with unexplained interstitial lung disease or respiratory insufficiency. The presence of pulmonary comorbidity is the most important prognostic factor in antisynthetase syndrome. The most severe pulmonary involvement occurs in patients with anti-PL7 and anti-PL12 antibodies, and in black patients with antisynthetase syndrome irrespective of antibody status.16 Patients with anti-SRP-positive immune-mediated necrotising myopathy may develop respiratory insufficiency.17 Patients with advanced inclusion body myositis may have reduced respiratory and swallowing function, leading frequently to pneumonia, hence the proposal to use non-invasive ventilation.18

There are no international guidelines on screening for interstitial lung disease in patients with myositis. Finding an antisynthetase syndrome-associated antibody should prompt pulmonary investigation, including vital capacity (supine and upright), diffusion capacity and high-resolution CT scan of the lungs. Pulmonary hypertension screening at diagnosis followed by annual echocardiography could be advised in line with existing guidelines for connective tissue disease.19

Cardiac comorbidity and management of cardiovascular risk factors

Cardiac comorbidity is relatively rare in idiopathic inflammatory myopathy, with an overall frequency of 9%.20 Associated cardiac disease is most common in patients with antisynthetase syndrome and anti-SRP-positive immune-mediated necrotising myopathy.4 Patients with inclusion body myositis have no increased risk of cardiac comorbidity.18

There are no international guidelines on screening for cardiac comorbidity in idiopathic inflammatory myopathy. Immunosuppressive drugs might positively influence the disease course, but even patients adequately treated with immunosuppressants or those in remission may develop cardiac problems.20 21

Patients with idiopathic inflammatory myopathies more often have risk factors for cardiovascular disease, such as hypertension, even without using corticosteroids.21 A risk factor such as smoking can have a greater negative impact in patients with myositis than in otherwise healthy patients, due to the already elevated risk of cancer or lung disease in some cases. Reducing these risk factors can be challenging as, for example, muscle weakness or impaired lung function impedes an active lifestyle and patients may be reluctant to use statins. The current advice is to prescribe statins in patients with idiopathic inflammatory myopathies according to the recommendations in the general population.22 We advise evaluating the serum creatine kinase before and after starting statin treatment, in order to avoid misinterpreting statin-induced creatine kinase elevation as a relapse of inflammatory myopathy. Statins (both medication and food supplements) are associated with anti-HMGCR-positive immune-mediated necrotising myopathy, but stopping the statin does not always lead to symptom improvement and anti-HMCGR immune-mediated necrotising myopathy may also occur in statin-naïve patients. However, we do not advise reintroducing statins in HMGCR patients with a history of statin use.

Skin involvement

Case 3: absence of classical skin changes

A 73-year-old man was referred with a 3-month history of progressive myalgia in the upper arms and legs. His walking speed had slowed and he had difficulty climbing the stairs and getting out of a chair. He had been using statins for 5 years but had stopped them 3 weeks before referral. He had lost 4 kg in the past 4 months; there was no dysphagia. There was itching redness of the scalp. Neurological examination showed slight redness of the face and neck, and symmetrical weakness of the deltoid, biceps, iliopsoas and hamstring muscles (Medical Research Council grade 4). The highest serum creatine kinase activity was 2656 U/L. Muscle biopsy of the vastus lateralis showed necrotic fibres, no perifascicular atrophy, diffuse Human Leukocyte Antigen upregulation and no cellular infiltrates (figure 3). We considered the diagnosis of immune-mediated necrotising myopathy and dermatomyositis, but the skin changes were atypical for both diagnoses. A myositis line blot showed anti-Mi2 autoantibodies. We performed cancer screening because of his age, weight loss and rectal blood loss but found no malignancy. We gave him corticosteroids, leading to a reduction of symptoms and serum creatine kinase to <100 U/L after 3 months of treatment.

Although the combination of statin use and necrosis in the muscle biopsy might have suggested immune-mediated necrotising myopathy, the presence of anti-Mi2 autoantibodies led to a diagnosis of dermatomyositis, despite the absence of classical dermatomyositis skin changes.

Figure 3

H&E staining of the muscle biopsy showing necrotic fibres.

Careful inspection of the skin, nails, nail folds and joints should be part of the physical examination of patients with suspected idiopathic inflammatory myopathy. The characteristic dermatomyositis features include heliotrope (purple) periorbital oedema, flat macules or patches (Gottron’s ‘sign’) or firm and raised (Gottron’s ‘papules’) on the extensor surface of the joints of the fingers. Furthermore, patients with dermatomyositis may have erythema of the chest and neck (V-sign) and upper back (shawl sign) (figure 4). Calcinosis is an invalidating symptom in dermatomyositis, associated with anti-NXP2 antibodies, especially in children. Patients with anti-MDA5-positive dermatomyositis may have atypical skin features, such as ‘mechanic’s hands’ (fissures and roughness with hyperkeratosis and scaling of the fingers; more commonly an antisynthetase syndrome-specific feature), ulceration and palmar papules. Of note, there are occasional cases of amyopathic dermatomyositis, so the isolated presence of a typical dermatomyositis rash can be a reason to perform autoantibody testing. Sclerodactyly can develop in anti-PL7-positive and anti-PL12-positive antisynthetase syndrome but can also result from the underlying connective tissue disease. Immune-mediated necrotising myopathy and inclusion body myositis have no associations with skin disease.

Figure 4

Skin changes in dermatomyositis (A: V-sign, B: periorbital oedema and rash, C: shawl sign) and antisynthetase syndrome (D: mechanic’s hands).

Dysphagia

Dysphagia can develop in all subtypes of idiopathic inflammatory myopathy, with an overall frequency of 39%.20 Apart from the impact on the social life of the patients, dysphagia may increase the risks of pneumonia, malnutrition and weight loss. In dermatomyositis, more pronounced dysphagia occurs with anti-TIF1-γ and anti-SAE1 antibodies. Dysphagia might also be prominent in myositis associated with a co-occurring autoimmune disorder, such as scleroderma. In patients with anti-SRP-positive immune-mediated necrotising myopathy, dysphagia occurs more frequently than in anti-HMGCR-positive patients, although in both groups dysphagia can be an important clinical feature.17 In patients with inclusion body myositis, dysphagia is common and is sometimes the initial symptom. Patients with inclusion body myositis who are anti-cN-1A seropositive have a higher adjusted mortality risk, possibly related to more pronounced bulbar weakness and worse pulmonary function.23 24

Approach to treatment

In general, idiopathic inflammatory myopathies respond well to immunosuppression; however, corticosteroids give significant side effects in over half of the patients and are frequently insufficient when given alone, such that patients need additional immunosuppressive treatment.25 The long-term outcome of patients with idiopathic inflammatory myopathies is often disappointing. Most (70%) have a chronic or polyphasic course, and a fair proportion of responders to treatment have residual disability and reduced quality of life.26 Corticosteroids are the first-line choice for all subtypes of idiopathic inflammatory myopathy except inclusion body myositis. Other immunosuppressive or disease-modifying antirheumatic drugs are usually added to avoid long-term corticosteroid use, if there is life-threatening comorbidity such as severe interstitial lung disease, and for most cases of immune-mediated necrotising myopathy due to their treatment resistance. When comparing immune-mediated necrotising myopathy associated with anti-HMGCR with anti-SRP, anti-SRP-positive patients remit less and relapse more during treatment (and might benefit from early treatment with rituximab), whereas for anti-HMGCR-positive patients intravenous immunoglobulins are preferred over rituximab.4 Rituximab is also more effective in patients with antisynthetase syndrome (mostly anti-Jo1) or those with dermatomyositis who have anti-Mi2 antibodies.27 There is no available evidence-based medical treatment for inclusion body myositis.

We need further studies to guide autoantibody-tailored treatment and to understand better the correlation between autoantibody titres and treatment response.

Prognosis

The prognosis for immune-mediated necrotising myopathy depends on extramuscular comorbidity and therapy resistance (as described above). However, it is difficult to predict the disease course in an individual. The previously described associated extramuscular symptoms are based on retrospective cohort studies, with variable data collection, ethnicity, antibody detection methods and treatment protocols. It is therefore important to interpret the assumptions about prognosis of specific forms of idiopathic inflammatory myopathies. In dermatomyositis, for example, anti-Mi2 and anti-SAE1 antibodies are generally associated with a good prognosis, due to little pulmonary involvement, less association with malignancy and a favourable response to treatment. However, in the Asian population, anti-SAE1 antibodies suggest a less favourable prognosis due to their association with cancer and interstitial lung disease.

Figure 5 summarises the previous paragraphs in a practice-based flow chart, including the analysis of autoantibodies.

Figure 5

A practice-based flow chart of the diagnosis of myositis, including the detection of autoantibodies. *Skin changes: consult a dermatologist to perform additional dermatological diagnostics, to enable omission of muscle biopsy. **Muscle biopsy can be omitted in case of classical skin changes in dermatomyositis and antisynthetase syndrome. ***Extensive screening includes vital capacity (supine and sitting), diffusion capacity, high-resolution CT scanning and pulmonary hypertension screening. ****Over a period of 3 years: yearly physical examination and positron emission tomography-CT or CT scan of the thorax/abdomen, mammography and ultrasound testes/pelvis; some clinicians perform repeated cancer screening in all patients with dermatomyositis and antisynthetase syndrome/non-specific myositis. CK, creatine kinase; .

Autoantibodies

Practical considerations

There are some caveats regarding autoantibody testing in idiopathic inflammatory myopathies.

  • First, using different techniques (figure 6) to detect autoantibodies makes it difficult to compare sensitivity and specificity, and concordance can be low.28 Immunoprecipitation is often considered the gold standard but is not available in many clinical laboratories. Recognising immunofluorescence patterns requires experienced staff, and there is a risk of differences between laboratories. The commercially available line blots using recombinant antigens are an excellent alternative to test multiple autoantibodies at the same time but are less sensitive for some autoantibodies (eg, anti-OJ can be false-negative on a line blot29). Test results can differ even when using one testing method: for example, the sensitivity of anti-cN-1A autoantibody detection in inclusion body myositis using ELISA varies between 37% and 76%, depending on the antigen used and the applied cut-off values.8 Specificity can vary as well, with anti-cN-1A autoantibodies found in 0%–11% of patients with dermatomyositis and in 4%–36% of patients with Sjögren’s syndrome, leading to a classification of anti-cN-1A as a myositis-associated antibody.30 31

  • Second, although autoantibody testing has become readily available through commercial line blots and ELISAs, some antibodies, such as anti-HMGCR and anti-cN-1A antibodies, are not included in commercially available line blots. Anti-cN-1A testing is not yet routinely available in many hospitals.

  • Third, the relatively low frequency of myositis-specific autoantibodies in patients (50%–80%) with idiopathic inflammatory myopathies may hamper accuracy in establishing the diagnosis. Thus, careful clinical evaluation and histopathological examination of tissue from an affected muscle are still important in differentiating between idiopathic inflammatory myopathies and non-inflammatory myopathies that can mimic them.10

Figure 6

Schematic representation of the laboratory techniques used to detect autoantibodies.

It is important to bear in mind that the relationship between autoantibody status and clinical characteristics is derived mainly from retrospective studies involving relatively small numbers of patients. We therefore urgently need prospective studies, including repeated measurements of autoantibody titres, to understand the relationships between disease activity and treatment.

Myositis-specific autoantibodies are mostly mutually exclusive in the individual patient and are rare among healthy controls.7 Finding multiple myositis-associated antibodies may be clinically relevant; for example, anti-Ro52 and anti-Jo1 frequently occur together, and this suggests a worse disease course for anti-Jo1-positive myositis.32

We do not recommend screening for antinuclear antibodies in patients with suspected idiopathic inflammatory myopathy. Apart from the limitations in the interpretation of immunofluorescence patterns as mentioned above, antinuclear antibodies can occur in healthy (especially elderly) people and in people with malignancies or infections. The sensitivity is limited as well: antinuclear antibody immunofluorescence can be negative in patients with myositis-specific antibodies, for example where there is anti-Jo1, anti-MDA5 and anti-HMGCR positivity.33 Positive antinuclear antibodies in a patient with suspected idiopathic inflammatory myopathy should lead to further analysis to know which myositis-specific or myositis-associated antibody is present.

Pathogenesis

The relatively limited specificity of some autoantibodies raises the question of whether the autoantibody is an autoimmune epiphenomenon or whether it is directly pathogenic. The evidence tends to favour direct pathogenesis. Enhanced expression of certain target autoantigens in regenerating muscle or in response to environmental factors (such as ultraviolet radiation) may induce or enhance the autoimmune response; the chemoattractant properties of some autoantigens can further propagate this. The tissue-specific autoimmune reaction could be explained by the cleavage of proteins into antigens with more autoantigenic features by tissue-specific enzymes such as granzyme B.34 The direct role of autoantibodies in the pathogenesis of idiopathic inflammatory myopathy is shown, for example, by passive immunisation of mice with IgG from anti-cN-1A-positive patients with inclusion body myositis, leading to histological changes resembling those seen in inclusion body myositis.35 Similarly, in immune-mediated necrotising myopathy, anti-SRP and anti-HMGCR activate humoral immunity via the classical pathway of the complement cascade, causing deposition of sarcolemmal C5b-9 and necrosis of muscle fibres.36 Some autoantibodies, such as anti-MDA5, anti-SRP and anti-HMGCR, show a correlation between antibody titre and clinical severity of the disease.37–39

Similarly, for myositis-specific antibodies in cancer, is the cancer a consequence of the autoimmune disease (eg, due to a certain genetic background or the use of immunosuppressive drugs) or does cancer cause an autoimmune response (eg, due to ectopical expression of autoantigens or altered cleavage of proteins within a tumour)? Interestingly, the target antigens of cancer-associated myositis-specific antibodies are to some extent involved in cancer pathogenesis. For example, TIF1-γ has a role in tissue differentiation, DNA repair and tumour suppression.11 34 However, the presence of anti-TIF1-γ in patients with juvenile myositis is not associated with an increased cancer risk, so other coexisting mechanisms in the elderly should play a role as well in oncogenesis.

Future perspectives

Since idiopathic inflammatory myopathy is relatively rare, it is very important that we have prospective follow-up studies on large cohorts to obtain more insight into autoantibody/phenotype correlations, to correlate repeat measurements of autoantibody titre to disease activity, and to gain more insight into the pathophysiological mechanisms and treatment response. Storage of clinical data and biomaterials in a (inter)national database such as the EuroMyositis Registry may facilitate these studies. At the local level, the physician should consider storing the serum of seronegative patients. On discovery of novel autoantibodies or targeted immunotherapy, retesting of the stored serum may help with treatment decisions, but also will help the verification of eligibility for new drug trials that might in the future be stratified by antibody status.

Conclusions

Detecting myositis-specific autoantibodies aids the clinician in diagnosing and managing myositis, while bearing in mind the technical limitations of autoantibody detection and the importance of the correlation of laboratory findings to the clinical phenotype.

Key Points

  • In patients with suspected idiopathic inflammatory myopathy, autoantibody testing is important because it can relate to distinct phenotypes, comorbidities, treatment response and prognosis.

  • Autoantibody testing can be performed with a myositis line blot with additional testing of anti-HMGCR and/or anti-cN-1A.

  • Some patients with idiopathic inflammatory myopathy appear to be seronegative due to the relatively low frequency of autoantibodies and/or technical limitations of the applied laboratory tests.

  • Storing serum from an autoantibody-negative patient may help future testing for newly discovered autoantibodies.

  • Autoantibodies can help the diagnosis and treatment of patients with slowly progressive ‘limb girdle muscular dystrophy’ without genetic diagnosis, or those with unexplained interstitial lung disease.

Acknowledgments

We thank Prinses Beatrix Spierfonds for the financial support on the previous work on this subject, and Dr B Kusters, neuropathologist, Radboudumc, Nijmegen, The Netherlands, for the muscle biopsy image and interpretation in case 3.

References

Footnotes

  • Contributors AR and JL wrote the initial version of the manuscript, which was reviewed and partially rewritten by MdV, AvdK, BvE, OB, GP and CS.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests GP and BvE are inventors of a patent (EP20120740236) licensed to Euroimmun AG, and GP received financial support from Euroimmun for his research programme. BvE reports a grant from Prinses Beatrix Spierfonds and personal fees and non-financial support from Fulcrum, personal fees from Facio, and grants from European Union’s Horizon 2020 research and innovation programme (Murab), Netherlands Organisation for Scientific Research (NWO), The Netherlands Organisation for Health Research and Development (ZonMw), Global FSH, Stichting Spieren voor Spieren, Dutch FSHD Foundation, and Association Française contre les Myopathies, outside the submitted work. JL and AvdK report grants from CSL Behring for an interventional study, outside the scope of this review. MdV serves as a consultant for Bristol-Myers Squibb. OB serves as a consultant for Novartis, Neovacs and CSL Behring.

  • Patient consent for publication Obtained.

  • Provenance and peer review Commissioned; externally peer reviewed by Jon Walters, Swansea, UK.

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