| Abstract|| |
Diagnosis of inflammatory myositis has been made easier with the availability of commercial assays for myositis-specific and myositis-associated antibodies. Clinico-serological association studies have permitted a better definition of clinical subsets. Myositis-specific auto-antibodies are highly specific and non-overlapping, whereas myositis-associated antibodies are those seen also in other connective tissue disorders such as systemic lupus erythematosus, primary Sjogren's syndrome, and idiopathic pulmonary auto-immune fibrosis. Their value is pronounced when clinical features are subtle or non-specific or when the muscle is not the primary organ involved. Overall, the muscle-specific and myositis-associated antibodies have changed the landscape in terms of diagnostic utility, prognostication, and the approach to organ-specific evaluation and management of idiopathic inflammatory myopathies (IIMs).
Keywords: Clinical features, inflammatory myopathy, myositis profile
|How to cite this article:|
Shobha V, Rajasekhar L. Current approach to diagnosis of inflammatory myopathies: Clinical features and myositis antibody profiles. Indian J Pathol Microbiol 2022;65, Suppl S1:252-8
|How to cite this URL:|
Shobha V, Rajasekhar L. Current approach to diagnosis of inflammatory myopathies: Clinical features and myositis antibody profiles. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:252-8. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/252/345039
| Introduction|| |
Inflammatory myopathy (IM) or myositis is what should be the right term to define the heterogeneous group of disorders which were earlier bound together by the presence of proximal muscle weakness, but they are no longer! There are more questions than answers on this subject. We have come a long way from the 'Bohan and Peter' classification times to the current American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification published in 2017. The spectrum of IM has expanded far beyond the classic description of muscle disease to include those with isolated or associated cutaneous disease without any significant muscle diseases. Another important subset which has evolved in the past decade or so is lung disease associated with muscle-specific antibodies (MSAs) or myositis-associated antibodies (MAAs). The term IM currently includes lung diseases such as anti-synthetase syndromes and a few others which may or may not have any muscle disease at all. It also includes hypomyopathic and clinically amyopathic dermatomyositis (DM). Our understanding about the constellation of these disorders is still evolving, and at present, they are tied together by variable degrees of muscle disease, skin manifestations, lung disease, and histopathologic features in association with one or the other MSA/MAA.
In this article, we present the evolution of the classification criteria and the clinical spectrum of diseases identified as IM. The categories of inflammatory myositis are presented with their distinguishing clinical, serologic, and histopathologic features. The auto-antibodies associated with this group of diseases are described in detail.
Classification criteria for IM are a work in progress. In 1975, Bohan and Peter classified patients with inflammatory muscle disorder into five groups: polymyositis, DM, myositis associated with connective tissue disease (CTD), cancer, and juvenile DM. With time, it was realized that within these groups existed patients with varied phenotypes. Some patients with the phenotype of polymyositis had severe necrotizing myositis on histopathology, and in some, rash of DM was seen, but muscle disease was not evident. Soon, antibodies unique to patients with IM came to be discovered and reported, with them being mostly absent from sera of patients with other CTD. Often, these antibodies better defined the phenotype of patients with IM. Hence, criteria were revised with times and by groups consisting of predominant neurologists or rheumatologists or pathologists and often under the umbrella of the European Neuromuscular Centre. In 2017, however, the International Myositis Classification Criteria Project (IMCCP) comprising rheumatologists, pediatric rheumatologists, neurologists, dermatologists, epidemiologists, and biostatisticians published a new criteria set. These criteria had items which were scored, and the sum determined the probability of a patient having IM. These criteria were the first to include the presence of anti-Jo-1 as a criteria item. Very soon, they were being criticized for not including other well-established antibodies such as the other anti-synthetases, anti-Mi2, etc., and for not giving weight to necrotizing myositis. The limitations of exponential growth in the discovery of myositis-specific and myositis-associated antibodies outstripping the classification criteria were realized. Hence, it is important to understand how the discovery of these antibodies shapes our understanding of IM.
| Clinical Features of IM|| |
The classic description of muscle weakness in IM is that of proximal upper and lower extremities as determined by manual muscle testing (MMT) or other objective strength testing, which is somewhat symmetrical, present on both sides, and is usually progressive over time. Muscles involved in flexion of the neck are more affected than the extensors. As this is a disease of skeletal muscles, the other group of muscles which can be affected are pharyngeal muscles, upper esophageal muscles, muscles of respiration, and diaphragmatic muscles. For unknown reasons, the skeletal muscles in distal groups and muscles of the face and orbit are spared. Compared to the diseases of peripheral nerves and anterior horn cells in the spinal cord, the muscle atrophy is not spectacular or noteworthy. In inclusion body myositis, the weakness involves the knee extensors, ankle dorsiflexors, and finger flexors more than the hip flexors. Severe and rapid onset weakness can be occasionally seen, which may signify an underlying rhabdomyolysis, especially in patients with immune-mediated necrotizing myositis. In polymyositis, the onset and progression of muscle weakness are more sub-acute.
There are only three pathognomic-named cutaneous lesions described in association with IM, namely, heliotrope rash, Gottron's rash, and Gottron's papules. Heliotrope rash is purple, lilac-colored, or erythematous patches over the eyelids or in a periorbital distribution, often associated with periorbital edema. Gottron's papules are erythematous to violaceous papules over the extensor surfaces of joints, such as finger joints, elbows, knees, malleoli, and toes. Gottron's sign is macules in the same distribution.
There are numerous other skin lesions which have characteristic association with myositis. Recent association with myositis-specific antibodies have been identified. The presence of classic rash in the absence of myositis has been proposed as a novel entity adermatopathic DM. Those with minimal or no muscle weakness are termed as hypomyopathic DM or clinically amyopathic DM (ADM), respectively. Cutaneous ulceration, skin necrosis, palmar papules, and cuticular changes associated with minimal or absent muscle weakness are described in association with the MDA-5 subset. The presence of multiple areas of panniculitis sometimes with ulceration is also a feature which should lead to suspect DM. Certain MSAs (Mi-2, SAE) are associated with florid rashes as compared to others. However, cutaneous involvement can be subtle, and atypical rashes are described.
An important subset which has evolved in the past decade or so is myositis in which the predominant organ involved is the lung and not the muscle. Lung disease can be manifested in many forms such as cryptogenic organizing pneumonia, interstitial lung disease (ILD), and rapidly progressive ILD, to name a few. Sometimes, muscle disease may not be the predominant feature, and there may be subtle muscle weakness and mild elevation of muscle enzymes. In majority of these situations, any one of the MSAs/MAAs, especially anti-synthetase antibodies, the PM-Scl antibody, Ro-52, and MDA-5, may be identified.
Inflammatory arthritis can be the presenting manifestation of patients with the anti-synthetase syndrome where myositis may follow in due course. This arthritis may be severe and may initially be mistaken for seronegative rheumatoid arthritis. A unique subluxing arthritis of the hand joints has been described in patients with anti-synthetase syndrome (1. Oddis CV, Medsger TA, Cooperstein LA. A subluxing arthropathy associated with the anti-jo-1 antibody in polymyositis/dermatomyositis. Arthritis Rheumatism. 1990;33(11):1640–5).
| Categories of IM|| |
With the discovery of MSA and MAA, characterizing the clinical phenotype of inclusion body myositis, and identifying an IM with predominant necrosis sans inflammation, the prevalence of polymyositis as a subset of IM has reduced.
The characteristic rash of DM makes this diagnosis relatively sensitive and specific. In the absence of rash, a perifascicular atrophy on histopathology is used to define DM, although it has been reported in patients with the clinical phenotype of OM.
Overlap myositis (OM)
Until recently, OM was defined as inflammatory myositis in a patient with classical connective tissue disease (CTD) features. In systemic sclerosis (SSc), as many as 5-43% may have overlapping myositis, systemic lupus erythematosus (SLE) may be present in 4-16%, and rheumatoid arthritis (RA) may be present in 3-5%. Currently, OM is defined by one or more overlap features or certain MAAs with or without meeting the criteria for CTD. Cutaneous manifestations; suggestive laboratory features of SLE; Raynaud's phenomenon; and other features of vasculopathy such as digital infarct, pitted scars, ulcers, and gangrene should prompt evaluation for underlying CTD. Subtle skin tightness, puffy digits, sclerodactyly, and salt and pepper pigmentation should be actively sought, especially in those with associated MAAs as shown in the table below.
I Anti-synthetase syndrome is defined by the presence of one of the eight anti-synthetase antibodies along with a triad of arthritis, interstitial lung disease [Figure 1]a, and/or Raynaud's phenomenon. The cutaneous feature of note is the mechanic's hands or the hiker's foot [Figure 1]b and [Figure 1]c.
|Figure 1: (a): Bilateral interstitial thickening extending up to the pleura with sub-pleural honeycombing changes suggestive of interstitial lung disease. (b): Fissuring roughening of the skin of fingers noted especially on the radial aspect of lateral three fingers classic for the mechanic's hands. (c): Similar changes in the toes referred to as the hiker's foot|
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Immune-mediated necrotizing myositis (IMNM)
This group of muscle diseases is characterized by severe muscle weakness with rapid progression and very high muscle enzymes (usually >30-fold). These were previously identified by the term 'necrotizing myopathy' and are differentiated from polymyositis by the rapidity of their onset and fast-paced progression. The characteristic auto-antibody associations of this group are with the anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) myositis-specific auto-antibodies. Muscle biopsy histopathology distinctive features are the presence of plenty of necrotic muscle fibers scattered throughout the muscle biopsy, myophagocytosis, sparse inflammatory cells, and minimal or no perivascular or perimysial infiltrate.
| Auto-antibody in inflammatory myopathies and their associations|| |
Auto-antibodies associated with IIM can broadly be categorized into two major groups as represented in [Table 1]. The discovery of these antibodies over the past 2–3 decades has changed our outlook and brought to the forefront the heterogeneity of this spectrum of disorders. It has also provided an important non-invasive tool in diagnosis. Myositis-specific antibodies (MSAs), especially in high titers, are largely limited to patients with IIM. These are useful for the diagnosis as well as sub-classification because they have been shown to correlate with distinct clinical phenotypes. In contrast, myositis-associated antibodies (MAA) are those which are seen in IIM but are also associated with other auto-immune diseases. Hence, although they may help to define certain phenotypes and predict the disease course, they cannot be used for a definitive diagnosis of myositis.
|Table 1: List of myositis-specific antibodies and myositis-associated antibodies|
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Myositis-Specific Antibodies (MSA)
Methods of detection
Most MSAs were identified using the immuno-precipitation (IP) technique. This technique involves reacting the sera with radio-labeled K562 cell extracts, followed by gel electrophoresis, and then the use of mass spectroscopy to identify the protein bands obtained from individual sera. However, line immuno-blot (LIB) assays are the commercially available assays. Poor agreement has been found between LIB and IP.
In a very interesting paper, LIB assays from three different manufacturers were compared between 144 IIM and 240 controls. anti-Jo 1 was positive in 2.9%, and anti-Ro 52 was positive in approximately 30% of controls. There was a reasonable concordance among kits. There is a debate about considering IP as a gold standard for detecting MSA. There are doubts about the specificity of MSA/MAA detected by LIB; however, the sheer ease and availability of the test make it the one most in use in reporting phenotypes in myositis. A representative image of a myositis line immunoblot is shown in [Figure 2].
|Figure 2: LIB of the patient serum showing strong positivity for anti-Jo-1 antibodies|
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Data from around 1600 European patients with IIM reveal the presence of MSA/MAA in approximately 60% of patients. 80% of these had one MSA only. anti-Jo-1 was the most common. Anti-Mi2, anti-SAE, anti-TIFg, anti-MDA-5, anti-Jo-1, and anti-PMScl were strongly associated with cutaneous inflammation, whereas anti-tRNA synthetases, anti-MDA5, and anti-U1/RNP were associated with ILD. anti-TIFG and anti-NXP2 were associated with malignancy. The antibodies were detected using IP.
Data from 150 Indian patients with IIM MSA and MAA to 16 antigens were obtained by the line blot assay using Euroimmun (Luebec, Germany) as per the manufacturer's instructions: Mi-2α, Mi-2β, TIF-1γ, MDA5, NXP-2, SAE1, Ku, PM-Scl100, PM-Scl75, Jo-1, SRP, PL-7, PL-12, EJ, OJ, and Ro-52. For increasing the specificity of association, antibody positivity was defined by a blot intensity of 25 or more. anti-Jo-1 was the most frequent MSA (10%), whereas the MAAs (anti-Ro-52, anti-Ku, and anti-PMScl 75 and 100) were more frequent (44%). anti- TIF-1γ, SAE1, and EJ had no association with another antibody, whereas all other antibodies were significantly associated with more than one antibody.
In another study from North India, 60% of a cohort of 250 patients had an antibody in their serum. MSAs were more prevalent than MAAs, with anti-Jo-1 being the most common MSA at 10% prevalence.
Because IP is not available in more than a handful of centers worldwide, it is difficult to establish the sensitivity and specificity of the antibodies detected by immuno-blot, which is a user-friendly method of detection of antibodies, widely available, and thus an invaluable tool.
Frequencies of the antibodies may vary among ethnic groups, for example, a higher frequency of anti-MDA5 antibodies in Chinese IIM and a lower frequency of anti-ARS antibodies compared to Japanese IIM, and may be driven by environmental and or genetic differences.
Role in prognosis/determining clinical course
The association of malignancy and dermatomyositis is well established. By 2010, enough data had accumulated, indicating that the presence of the anti-155/140 antibody in serum of IIM patients (detected for the first time in 2006) had a very high odds ratio for association with malignancy and a very high negative predictive value too. The other name of this antibody was anti-TNF-g antibody.
The anti-Mi2 antibody-associated DM patients are very responsive to steroid therapy and may have a monophasic course. The association with malignancy is variously mentioned as poor to good.
Auto-antibodies to SAE were present in very few patients in a 1637 strong cohort of patients but were strongly associated with any type of rash and periungual erythema.
In 2012, Ichimura reported a low prevalence of anti-NXP2 antibodies in adult IIM but a strong association with advanced malignancy either at diagnosis or within 3 years.
In 2013, Pluk reported that high concentrations of anti-Mup44 (cytosolic 5'-nucleotidase 1A) antibodies were seen in 33% of patients with sporadic inclusion body myositis (IBM) and lower concentrations in other IIM, marking it as a diagnostic aid.
Besides describing the presence of anti-SRP antibodies in 26 patients with IIM, Targoff et al. reported the rapid onset and unusually severe myositis in the absence of cutaneous inflammation and lung fibrosis, marking it as a subset of PM.
In patients with IMNM, in those with anti-HMGCR Ab, the subset of patients with no prior statin exposure were men with less frequent dysphagia but more difficult-to-treat disease. These data came from 64 patients with IMNM.
Auto-antibody negative subsets of IIM
With the help of emerging data sets, it is now reasonably well established that up to 30% of patients with IIM have no associated antibodies. This is especially true in the subsets of DM and statin-related IMNM. Seronegative IMNM patients were more often female and had extra-muscular disease more often. It is quite likely that these patients have antibodies waiting to be discovered.
| Diagnosis|| |
Currently, clinicians use EULAR/ACR classification criteria for diagnosis of IIM, which is a robust validated and weighted score. It takes into consideration four specific muscle biopsy features, classic cutaneous manifestations, and auto-antibodies. A web-based calculator can be used to derive the diagnosis and further classify patients into polymyositis (PM), IBM, ADM, DM, or juvenile dermatomyositis (JDM). The muscle biopsy features which are used in this classification are endomysial infiltration of mononuclear cells surrounding, but not invading, myofibers (weighted score-1.7), perimysial and/or perivascular infiltration of mononuclear cells (1.2), perifascicular atrophy (1.9), and rimmed vacuoles (1.9). Using this classification, a score of ≥7.5 (≥8.7 with muscle biopsy) is categorized as 'definite IIM'. In these criteria, weightage is given to symmetric involvement of the lower limb, the upper limb, neck weaknesses, and dysphagia. Cutaneous features receive a lot of weightage. Elevated muscle enzymes also receive weightage, and so do the histopathology. However, electromyography (EMG) does not find position as an item. A current pragmatic approach to diagnosis of inflammatory myositis is delineated in [Figure 6].
|Figure 6: Suggested clinician's approach to diagnosis of inflammatory myositis. EMG: electromyography, DM: dermatomyositis, PFA: perifascicular atrophy, ANA anti-nuclear antibodies, MSA: myositis-specific antibodies, MAA: myositis-associated antibodies, OM: overlap myositis, IMNM: immune-mediated necrotizing myositis, IBM: inclusion body myositis|
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In a patient with classical clinical presentations such as sub-acute onset of proximal myopathy or classical DM rash or muscle biopsy features, the diagnosis is relatively straightforward. However, mimickers such as drugs/toxins, endocrine myopathies, late onset muscle dystrophies, and infections can pose challenges to diagnosis.
| Learning Through Cases|| |
Case scenario 1
A middle-aged lady presented with classic DM rash of a heliotrope around the eyes and Gottron's papules on the knuckles and dorsum of fingers [Figure 1]a and [Figure 1]b, symmetric proximal muscle weakness, and elevated muscle enzymes. The diagnosis of DM is confirmed with this information. Muscle biopsy in this patient does not add to diagnosis, prognosis, or therapeutic decisions. Magnetic resonance imaging muscles confirmed the presence of inflammatory myositis, but again, it was not essential to improve the diagnosis or prognosis. The auto-antibody against Mi2 was positive in high titers. This may suggest a good prognosis. Even in the absence of resources to detect antibodies, it is a good clinical practice to follow up these patients as therapy is de-escalated over months to years for a relapse of myositis or development of cancer (for at least 3 years).
Case scenario 2
A 32-year-old lady [Figure 3]a and [Figure 3]b presented with long-standing Raynaud's phenomenon, occasional pain in finger joints, fingertip pitted scars, telangiectasias on the face, and recent onset of proximal muscle weakness. Her anti-nuclear antibody (ANA) was strongly positive, a fine speckled pattern. Her muscle enzymes were elevated, the extractable nuclear antigen blot was 3+ for RNP/Sm, and nail fold capillaroscopy showed capillary dropouts, hemorrhages, and a distorted capillary architecture. This patient was diagnosed as overlap myositis as she had evidence of muscle inflammation and suggestive clinical and laboratory features of scleroderma.
|Figure 3: Anti-TIF-gamma-associated DM. Cutaneous inflammation over the face, nasolabial fold, and anterior surface chest|
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Case scenario 3
Clinically amyopathic dematomyositis (CADM)
A 21-year-old lady [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d presented with fever, erythematous rashes on the malar area, upper eyelids, and papules on proximal inter-phalangeal joints and in palmar creases with erythema of nail beds and inflammatory polyarthritis since 2016. A year later, she developed proximal muscle weakness with severe pharyngeal involvement with cutaneous flare and arthritis. Her creatine phosphokinase was elevated, and Electromyoneurogram (ENMG) was suggestive of myopathy. Muscle biopsy revealed perifascicular atrophy. ANA IF showed an intense mitotic chromosomal coat pattern.
|Figure 4: (a) Right index finger pallor phase of Raynaud's phenomenon and digital tip infarcts in most fingers. (b) Pinched nose and thin lips suggestive of scleroderma facies|
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In 2018, she experienced another cutaneous flare that was associated with cuticular infarcts, telangiectasias, heliotrope rash, malar rash, and digital tip ulcers. Further, a year later, she developed multiple cutaneous ulcers over both upper and lower limbs and the trunk with secondary infection, vasculitic rash over palms, and left index finger ischemic changes. There was no muscle weakness. This presentation with cutaneous inflammation followed at a variable period of time with muscle involvement is characteristic of anti-MDA 5 myositis, also referred to as clinically amyopathic DM. Her immuno-blot was strongly positive for MDA5++ and RO52++.
Case scenario 4:
A 55-year-old lady [Figure 5], carrying a diagnosis of the adenocarcinoma ovary, was hospitalized with erythematous, edematous rashes all over the trunk, proximal limbs, face, and neck with areas of exfoliation. She was bed-bound because of extreme muscle pain. Her muscle enzymes were marginally elevated. Her myoblot/immuno-blot was positive for TIF1-γ, which has a strong association with cancer-associated myositis. This is an auto-antibody directed against 155 kDa nuclear protein, identified as transcription intermediary factor 1-gamma (TIF1-γ). The presence of this auto-antibody substantiates the diagnosis and precludes the need for muscle biopsy in a sick patient.
|Figure 5: Anti-MDA5 antibody DM. (a): Multiple ulcers in the axilla. (b): Secondary changes of hypopigmentation depigmentation over healed ulcer at the elbow. (c): Inverse Gottron's sign – erythema over the palmar areas and tender erythematous nodular vasculitic lesions over the palms. (d): Nail fold infarct, fingertip ischemia|
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Conflicts of interest
There are no conflicts of interest.
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Department of Clinical Immunology and Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]