Inflammatory Myopathy

Disease/Disorder

Definition

Idiopathic inflammatory myopathies (IIM) are a group of autoimmune disorders characterized by chronic inflammation of the muscle. They have varying clinical and extramuscular manifestations. Muscle weakness, poor endurance, and myalgia are commonly seen clinical manifestations, whereas, skin rash, arthritis, interstitial lung disease (ILD), and cardiac involvement are commonly seen extramuscular manifestations.¹ Diagnosis is made through these manifestations along with the presence of autoantibodies that are specific for myositis, called myositis-specific autoantibodies (MSAs). MSAs are present in up to 60% of patients with IIM, and the most common are anti-Ro52, anti-PM-Scl, anti-Ku, and anti-U1RNP. Some of these MSAs may also be present in other rheumatological disorders such as systemic lupus erythematous (SLE), systemic sclerosis, or Sjogren syndrome. About 20-30% of patients with IIM have no known MSAs and are classified as seronegative IIM.¹

Over the years, as more has become known about IIM, new classifications and subtypes have been developed. In the 1800s, the term polymyositis (PM) was used for these disorders. Dermatomyositis (DM) was identified in 1863 in these patients who also had a skin rash. Clinical definitions were not made until the 1950s for PM and DM. Eventually IIM were divided into subgroups based on clinical and histopathological manifestations of the muscle tissue. These subgroups were DM (juvenile and adult onset), PM, inclusion body myositis (IBM), and amyopathic DM (ADM).¹ Later, new subgroups were identified based on MSAs making the diagnosis of PM controversial. These subgroups include antisynthetase syndrome (ASyS) in the 1990s and immune-mediated necrotizing myopathy (IMNM) in 2006. Additional subgroups are cancer-associated myositis and overlap myositis.¹ Patients who originally were diagnosed with PM, now are felt to have one of these other subtypes, meaning that the number of patients who have PM is actually very small.¹

Juvenile-onset IIM are rare, serious chronic conditions, with the most common occurring one being juvenile DM.² Juvenile-onset IMM differs from adults in several ways including greater presence of subcutaneous calcification, less disease damage, lack of association with cancer, increased risk of vasculitis, and different autoantibody associations.³

Clinical signs and symptoms, muscle biopsy features, MRI findings, serological assessment, and serum levels of muscle enzymes are all used in the diagnosis of IIM and its subtypes. Treatment consists of high dose glucocorticoids along with immunosuppressive drugs; however, treatment responses vary.¹ Further research is needed as most of the past research focused on the previously classified subgroups of PM, DM, and IBM. They did not account for the newer MSA-defined subtypes which may skew previous data.¹ There are several different conditions that may mimic myositis including muscular dystrophies, metabolic myopathies, mitochondrial myopathies, endocrine myopathies, and toxic myopathies.¹ Muscle weakness is a non-specific symptom and may lead to misdiagnosis, especially when skin manifestations and/or MSAs are absent. Medical history, physical examination, electromyography, laboratory, muscle biopsy, and genetic testing are key in making an accurate diagnosis.

Etiology

Interactions between genetic and environmental risk factors are thought to be the cause of the IIM phenotypes. There appears to be both adaptive and innate immune mechanisms and non-immune mechanisms involved in the different types of IIM, though the understanding of these processes is limited.¹ Of note, pathological observations made early on in patients with the diagnosis of PM, now would be classified as having ASyS or IMNM, making the data inaccurate. There is about a 20% increased risk of heritability between first-degree relatives.⁴

Epidemiology including risk factors and primary prevention

Estimates on prevalence and incidence as well as risk factors vary greatly from studies taken from Asia, Europe, and North America. Estimates of new cases of IIM range from 11 to 660 per 1,000,000 person-years and between 2.9 and 34 people per 100,000 population.¹ DM, PM, and IMNM occur more commonly in women than in men. Incidence increases with age with a peak age of around 50 years old.¹ Ethnic minority groups have an increased risk of anti-SRP autoantibody-related disease, increased cardiovascular risk, and a higher risk of juvenile PM/juvenile connective tissue myopathy. African American children with juvenile DM have an increased risk of calcinosis.¹ In juvenile-onset IIM, ethnic minorities are more likely to have cardiovascular and cerebrovascular comorbidities.²

There are several risk factors that have been associated with IIM. Lower respiratory and gastrointestinal infections have been implied as risk factors for PM and DM. Co-occurrence of HIV or human T cell leukemia virus type 1 have been linked to PM, DM, and IBM.¹ Hepatitis B has also been seen in patients with PM. An association has been found with UV radiation and DM, and there is an association of smoking with anti-Jo1 auto-antibody-positive ASyS.¹

Genetic risk factors have also been suggested. It is believed that specific HLA haplotypes are associated with the development of IIM and their subsets.⁵ A large study done by the Myositis Genetics Consortium found a strong association among alleles of the 8.1 ancestral haplotype and PM and DM.¹ Some non-HLA loci have also been associated with IIM in Europe.¹

Patho-anatomy/physiology

It is felt that the pathogenic pathways differ between the various phenotypes due to them having different clinical features, responses to treatment, and outcomes.¹ CD26 has been selectively shown in IIM patients’ muscle cells, particularly in tissues presenting greater necrosis and vascular inflammation.⁴ IMNM and IBM predominately affect skeletal muscle and have similar histopathological features found on muscle biopsy.¹ DM and ASyS are multi-organ diseases that affect the skin, lungs, and/or joint. They share similar histopathological features, however, they each have a unique gene expression profile.¹ DM has a higher expression of type 1 interferon-inducible genes than in ASyS. Transcriptomic data alone can be used to identify patients with DM, ASyS, IMNM, or IBM with > 90% accuracy.¹

Dermatomyositis (DM)

The typical histological features seen on muscle biopsy in DM are perifascicular myofiber abnormalities, including atrophy and necrosis. One study showed that endomysial capillaries in regions of perifascicular atrophy were reduced in number and size and that the remaining endothelial cells stained positive for components of the activated membrane attack complex in patients with DM.¹ Though it is unsure as to whether membrane attack complex deposition was the cause or effect of endothelial damage in DM. The abnormal perifascicular regions are located near areas of perimysium with infiltrating inflammatory cells and remnants of blood vessels.¹ In patients with DM, type 1 interferon-inducible genes are among the most upregulated in the muscle, skin, and peripheral blood. JAK – STAT inhibitors target this pathway and are effective in treating DM-related damage to the skin, muscles, and lungs.¹

Antisynthetase Syndrome (ASyS)

ASyS is characterized by autoantibodies against one of many aminoacyl transfer RNA (tRNA) and is associated with muscle and lung damage. Patients with ASyS had more areas of perifascicular necrosis on muscle biopsy than those with DM (79% to 35%).¹ Endomysial infiltration by clonally expanded T cells were also found in ASyS, similarly to patients with IBM. CD4+ T cells with reactivity against histidyl-tRNA synthetase are present in the lungs and blood in ASyS.¹

Immune-Mediated Necrotizing Myopathy (IMNM)

3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP) are the autoantibodies most commonly seen in patients with IMNM. Autoantibodies against HMGCR and SRP histologically indistinguishable from other another on muscle specimens, and gene expression profiles show only minor differences.¹ Greater than 70% of patient with IMNM have the HLA class II DRB1*11:01 allele present. Anti-HMGCR and anti-SRP auto-antibody titers are highly correlated with muscle weakness and elevated levels of creatine kinase.¹

Inclusion Body Myositis (IBM)

In patients with IBM, there is a frequent occurrence of autoantibodies recognizing the NT5C1A protein in the blood.¹ There is evidence that muscle damage is mediated by T cells in that cytotoxic CD8⁺ T cells surround and invade the muscle fibers in patients with IBM. The lymphocytes seen in IBM are like those seen in T cell large granulocytic leukemia in that the infiltrating T cells have increased cytotoxic potential and resistance to apoptosis. This is the likely reason that patients with IBM are refractory to treatment with glucocorticoids and other immunomodulatory therapies.¹

Polymyositis (PM)

PM is defined as a myositis phenotype with chronic muscle weakness without skin involvement. It involves predominant cytotoxic T cell mechanisms.¹ With the discovery of new classifications of IIM, it is believed that PM has been over diagnosed, with most patients now being classified as having IBM, IMNM, or ASyS. There is only a small subset of patients with IIM who do not have DM, ASyS, IBM, IMNM, or myositis autoantibodies who do have the classic clinical and pathological findings of PM.¹ It is now believed for this reason that PM is very rare, occurring far less than was originally thought.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The onset of IIM may be acute, subacute, or chronic.

Mortality estimates vary from studies from Europe, North America, and Japan. A large population-based cohort study done in Norway, compared the death rates of 326 patients with IIM diagnosed between 2003 and 2012 with death rates of the general population and found a mortality ratio of 2.4, 2.6, and 1.7 respectively for PM, DM, and IBM.¹ Another study showed that overall mortality is the highest during the first year after diagnosis, and then decreases in patients diagnosed with IIM.¹ A study looking at mortality in patients with juvenile-onset IIM found a standardized ratio of 14.4 with risk of mortality being the highest for juvenile connective tissue disease-associated myositis, followed by juvenile PM, then juvenile DM.²

Specific secondary or associated conditions and complications

Malignancy, cardiovascular disease, lung disease, and infections are the leading causes of death in patients with IIM.^1,4 All subgroups of adult-onset IIM have a twofold to sevenfold increased risk of malignancy compared to the general population, except for ASyS and IBM.¹ For this reason, cancer screening is crucial. The highest risk is within 1 year before and 1 year after IIM diagnosis,^1,5 but patients may remain at risk for up to 10 years in some subgroups.¹ The risk is exceptionally high amongst patients with DM, specifically in those with anti-TIF1 or anti-NXP2 autoantibodies.^1,3 Other risk factors include older age at onset, male gender, dysphagia, cutaneous necrosis, rapid disease onset, and resistance to immunosuppressive therapy.³ The risk is also high in those with autoantibody negative IMNM.¹ The most common malignancies seen in patients with IIM are lymphoma and cancers of the lung, breast, and ovary.¹ Cancer screening is not warranted in the pediatric population.³

There is an increased incidence of hypertension, diabetes, dyslipidemia, obesity, and coronary artery disease (adult-specific) associated with IIM.³ Screening for adults consists of serum cardiac markers (troponins), ECG, echocardiography, and cardiac MRI. For pediatric patients with IIM, ECG and echocardiography can be considered.³ Cardiac abnormalities are frequent at disease onset in children, however, they are rarely serious and long-term damage is rare.²

ILD is the major cause of mortality and morbidity in myositis, specifically in patients with ASyS.¹

Fracture risk is high in IIM due to glucocorticoid use, female preponderance, and average age of onset for adult disease.³ A bone health assessment should be routinely performed. Studies have shown that patients with juvenile DM have an increased risk of vertebral fractures.³ It is important to look for signs of connective tissue disease overlap as it is associated with increased risk of mortality.³

In juvenile-onset IIM, children with recent onset of puberty during the active phase of treatment or previous growth failure had an increased risk of delayed pubertal development with further growth retardation.²

Essentials of Assessment

History

Dermatomyositis (DM)

DM is defined by myositis and the characteristic cutaneous manifestations. Classic DM has muscle and skin involvement, whereas in ADM there is no muscle disease.¹ Hypomyopathic DM is when there are no muscle symptoms despite laboratory evidence of myositis. ADM and hypomyopathic DM are defined as symptoms lasting > 6 months and are collectively termed as clinically ADM (CADM). CADM has the same skin manifestations that are seen in DM. They can still have systemic involvement such as ILD and dysphagia.¹ Malignancy has been linked with DM (cancer-associated DM).¹ Pain is a common complaint in juvenile DM. Studies have shown that patients with juvenile DM have poorer physical and psychological well-being compared to healthy cotrols.²

Antisynthetase Syndrome (ASyS)

ASyS is a multisystem disease, although myositis is not always present. The most frequent manifestation is ILD. It is usually chronic and often progressive.¹

Immune-Mediated Necrotizing Myopathy (IMNM)

IMNM is characterized by proximal muscle weakness that is in a symmetrical distribution. It has extremely high muscle enzyme serum levels, a myopathic pattern seen on electromyography, muscle specimens showing necrosis or regeneration with minimal lymphocytic infiltrates. Systemic manifestations such as rash, arthritis, or ILD are rarely seen in IMNM.¹

Inclusion Body Myositis (IBM)

IBM is characterized by asymmetrical weakness of both proximal and distal muscles. The quadriceps and long finger flexors are commonly affected. It occurs mainly in individuals over the age of 50.¹ Extramuscular manifestations are rare, though dysphagia occurs in greater than 50% of patients. It progresses slowly over decades and does not usually respond to immunosuppressive therapy.¹ Hallmark histopathological findings include endomysial T cell infiltration and rimmed vacuoles. It has been associated with Sjogren’s syndrome, as well as other connective tissue disorders. There has been a reported association to sarcoid myopathy.¹ Survival rates are decreased compared to matched populations of healthy patients and other patients with IIM. Respiratory failure and pneumonia are common causes of death in patients with IBM.⁴

Polymyositis (PM)

PM is now considered a rare form of IIM. Of note, most patients who were previously classified as having PM can now be classified as having ASyS, IMNM, IBM, or overlap myositis. PM is characterized by an inflammatory disease in the proximal muscles with the absence of skin involvement.¹

Overlap Myositis

Overlap myositis occurs when myositis overlaps with other connective tissue disorders such as systemic lupus erythematosus, systemic sclerosis, Sjogren’s syndrome, or rheumatoid arthritis. Patients who have features of both scleroderma and myositis are referred to as having scleromyositis. Head drop and distal weakness are commonly seen.¹

Physical examination

The most typical clinical presentation seen in a patient suspected of having IIM is proximal muscle weakness with a symmetrical distribution, sometimes accompanied by pain. Both upper and lower extremities can be involved, with the hip and thigh muscles most likely being involved. The neck flexors are characteristically involved, and sometimes the extensors. Difficulty getting up from a seated position, climbing stairs, or raising their arms over their head are common complaints of patients with IIM.¹ Muscle involvement may be lacking in DM and ASyS. Patients may present initially with extramuscular symptoms, especially skin rash, polyarthritis, and ILD.¹

Skin Manifestations

• In DM, highly characteristic skin lesions include heliotrope rash (periorbital violaceous erythema associated with edema), Gottron papules (erythematous to violaceous papules, Gottron sign (macules overlying the extensor surfaces of joints, V sign (erythema over lower and anterior neck and upper chest), and shawl sign (erythema over posterior shoulders, neck, and upper back).¹ Periungual nailfold erythema with cuticular punctate hemorrhage is often seen as well. Poikiloderma (hyperpigmentation/hypopigmentation, telangiectasia, and atrophy) may occur because of these skin changes. Pruritis is also commonly seen in patients with DM.¹ Calcinosis (abnormal depositions of insoluble calcium salts found in skin and subcutaneous tissue) can be seen in both DM and juvenile DM. They occur in areas exposed to microtrauma.¹
• Of note, patients with darker skin tones are under-represented in cutaneous education materials, specifically for DM. This can lead to under diagnosing and inappropriate exclusion from clinical trials due erroneous skin scoring.⁶
• The hallmark skin feature of ASyS is called mechanic’s hands (non-pruritic, hyperkeratotic eruptions on the lateral surfaces of the digits). Mechanic’s hands may also be seen in patients with DM and anti-PM-Scl autoantibodies.¹

Figure 1: Heliotrope rash, as seen is dermatomyositis.⁷

Figure 2: Gottron’s rash. This is the rash of dermatomyositis called Gottron’s rash. It is erythematous, overlying MCPs and PIPs. When it is raised and scaling, it is referred to as Gottron’s papules.⁷

Figure 3: Gottron’s papules. These hands show the classic rash of dermatomyositis with scaling rash over the MCPs and DIPs of the hands.⁷

Figure 4: Nailfold changes. This finger shows nailfold changes with hemorrhages/infarcts suggesting small vessel vasculitis/vasculopathy. This might be seen in connective tissue diseases such as lupus and dermatomyositis.⁷  

Images used by permission from RheumExam Atlas

Pulmonary Involvement

ILD is present in up to 78% of patients with IIM, typically in patients with ASyS and anti-MDA5 positive DM. Most patients with ILD in IIM have subacute or chronic courses.¹

Cardiac Involvement

Only about 10% of patients with IIM have clinically apparent cardiac disease, with subclinical involvement being more frequent up to 75%. Cardiac involvement consists of myocarditis, inflammatory infiltration in the cardiac conduction system, and replacement fibrosis.¹ Patients with DM and PM have a higher prevalence of supraventricular arrhythmias and new onset heart failure.⁴ The risk of heart failure has been found to be the highest during the first year following the diagnosis of IIM, but may persist for up to 10 years.⁴ Patients with overlap myositis and systemic sclerosis are more likely to have cardiac involvement.¹

Esophageal Involvement

Dysphagia is present in up to 60% of patients with myositis, most prevalently in patients with IBM. It is a risk factor for aspiration pneumonia in patients with IIM. Dry mouth may also be seen in patients with Sjogren’s syndrome.¹

Joint Involvement Arthritis is commonly seen, especially in patients with ASyS. It may be the presenting symptom in some patients. It is usually symmetrical and affects small joints of the hands. Because of this, it can be misdiagnosed as rheumatoid arthritis.¹

Functional assessment

Muscle weakness is evaluated by using manual muscle testing or via muscle endurance using a functional index. Routine pulmonary function assessments should be performed since abnormalities are frequent and often asymptomatic.

Laboratory studies

Serum levels of muscle-derived enzymes will be elevated in most active muscle disease. In IIM, serum levels of creatine kinase, aldolase, lactate dehydrogenase, and aspartate transaminase are often elevated; with creatine kinase being the most sensitive marker.¹ Although, creatine kinase can be normal in patients with DM, ASyS, or IBM.⁵ Of note, anti-nuclear antibody (ANA) can be found in about 50-65% of patients classified as having DM, IBM, or PM.⁵ As previously stated, MSAs are present in up to 60% of patients with IIM.¹ MSAs can help facilitate diagnosis, inform disease phenotype and prognosis, and may help tailor treatment.³ Serum cardiac troponins can be drawn to measure cardiac involvement. Troponin I levels are sensitive and specific measure of cardiac involvement. Troponin T levels may also be elevated due to inflammation in non-cardiac striated muscles.¹

Dermatomyositis (DM)

Most patients with DM have one of the following MSAs: anti-Mi-2, anti-melanoma differentiation-associated gene 5 (MDA5), anti-transcriptional intermediary factor 1 (TIF1), anti-nuclear matrix protein 2 (NXP2), or anti-small ubiquitin-like modifier activating enzyme (SAE) antibodies. Patients with anti-Mi-2 or anti-NXP2 DM tend to have prominent myositis, whereas patients with anti-MDA5, anti-TIF1, or anti-SAE DM are milder and often asymptomatic.¹

• Anti-Mi-2 has been associated with the classic DM phenotype with high creatine kinase levels, good response to treatment, and good prognosis. Although relapse is common. ILD is rare.¹
• Anti-MDA5 DM typically have no muscle disease (ADM) or mild muscle disease. It is strongly associated with ILD. Arthritis is common and patients often have characteristic cutaneous manifestations such as palmar papules and deep ulcerations over the joints.¹
• Anti-TIF1 DM is characterized by an extensive rash with relatively mild myositis. Dysphagia is frequently seen and can be severe. It is associated with a high risk of malignancy.¹
• Anti-NXP2 DM is characterized by prominent muscle disease and have increased risk of calcinosis. Cutaneous manifestations are relatively modest and may be absent (DM sine dermatitis). Anti-NXP2 DM also has been associated with a high risk of malignancy.¹
• In anti-SAE DM, skin manifestations usually proceed muscle manifestations, the rash may be extensive, dysphagia is common, and patients may have mild ILD. An association with malignancy has also been reported.¹

Antisynthetase Syndrome (ASyS)

Antisynthetase auto-antibodies bind to and inhibit the function of aminoacyl-tRNA synthetases. There have been eight autoantibodies identified in patients with ASyS.¹ Patients with anti-PL-7 or anti PL-12 autoantibodies have a higher rate of ILD and higher mortality than those with anti-Jo1 autoantibodies.^1,4

Immune-Mediated Necrotizing Myopathy (IMNM)

IMNM has the following 3 subgroups: anti-HMGCR, anti-SRP, and autoantibody negative IMNM.¹

• Anti-SRP myopathy tends to have extramuscular manifestations, including dysphagia and cardiac involvement, and more severe muscle disease; then those with anti-HMGCR myopathy.¹

• Anti-HMGCR myopathy manifests as predominantly skeletal muscle disease without other organ involvement. It has been associated with statin use, though can also be found in individuals without previous statin use.¹

• Autoantibody negative IMNM is poorly described but is characterized by frequent occurrences of associated connective tissue disorders, especially systemic sclerosis. It also has higher rates of extramuscular manifestations than those with seropositive IMNM.¹

Inclusion Body Myositis (IBM)

Autoantibodies against cystoscolic 5’-nucleotidase 1A (cN1A or NT5C1A) have been discovered in patients with IBM.⁸ They have also been found in children with juvenile myositis and juvenile idiopathic arthritis. It has also been found in Sjorgen syndrome and systemic lupus erythematosus. For this reason, anti-cN1A autoantibodies may not be specific for IBM.⁸

Polymyositis (PM)

Due to recent reclassification, there is no specific autoantibody associated with PM.¹ However, there has been identification of a possible new MSA targeting eIF3 (a cytoplasmic complex with a role in translation initiation) that would identify a PM subset not related to malignancy or ILD. It has a favorable response to treatment.⁵

Overlap Myositis

Anti-U1RNP, anti-Ku, anti-PM-Scl, anti-RuvBL1, anti-RuvBL2, anti-Ro/SS-A, and anti-La/SS-B are autoantibodies that have all been detected in overlap myositis. Extramuscular manifestations are seen at an increased rate in patients without scleroderma-associated autoantibodies.¹

Cancer-Associated Myositis

A possible new MSA that targets heat shock factor 1 (HSF1) protein has been identified to mark cancer-associated myositis.⁵

Juvenile-Onset IIM

The presence of TIF-1, anti-HMGCR, anti-SRP, or anti-synthetase antibodies in juvenile-onset IIM may result in a more severe, chronic, or treatment resistant disease course.² Myositis associated anti-Ro52, anti-MDA5, and anti-synthetase autoantibodies are associated with increased risk of ILD; and anti-NXP2 is associated with an increased risk of calcinosis. The presence of Mi-2 autoantibody has been linked to a milder and shorter disease course with low mortality.²

Imaging

Imaging may be used to aid in the diagnosis and monitoring of myositis. MRI may be used to identify sites that can be targeted for muscle biopsy. A study done on IMNM that looked at whole-body MRI revealed that muscle damage was preferentially located in the lumbar and pelvifemoral region, and it correlated with disease duration.⁵ Fatty infiltration in the thighs in a proximal to distal gradient was found in IBM. This infiltration seen on MRI also correlated with histopathologic damage in IBM, while muscle edema correlated with the amount of inflammation.⁵ Ultrasound may also be used to assess muscles. Patients with IBM show higher echogenicity and lower muscle thickness than patients with DM or PM.⁵ Ultrasound of the deep finger flexors can help delineate patients with IBM from other myositis subsets.⁴

In anti-MDA5 autoantibody DM, acute rapidly progressive ILD may progress to adult respiratory distress syndrome and respiratory failure with poor prognosis. Perilobular opacities that can progress to ground glass consolidations may be seen on high-resolution CT. A non-specific interstitial pneumonia pattern seen on CT is considered a favorable prognostic factor.¹

A video swallow study can be performed to assess for dysphagia.^4,5

Cardiac MRI can detect inflammation in the myocardium or irreparable changes very early on in IIM, even when no symptoms are present.¹

Supplemental assessment tools

Electromyography (EMG) can identify myopathic changes to help distinguish myopathy from other neuropathic causes of motor weakness. It may also be useful in identifying muscle involvement in patients with mild or absent muscle involvement when extramuscular manifestations are present. EMG may detect abnormal electrical activities of muscle fibers and immune-mediated changes may be seen on muscle biopsy. EMG findings can be supportive of a diagnosis of IIM, but it is not diagnostic as many abnormalities are nonspecific. A study done on 50 patients with IBM, found that the shortness of motor unit potential duration correlated with all clinical measures, myotonic discharges correlated with the severity of inflammation.⁹

Dermatomyositis (DM)

A skin biopsy is recommended in patients without muscle involvement. Dermal mucin deposition, perivascular inflammatory infiltrates, dermatitis with dyskeratosis, and vascular dilation and/or damage can be seen on skin biopsy.¹ Muscle biopsy will show perifascicular atrophy with reduced number of capillaries. Patients with the classic histopathological features of DM on muscle biopsy but lack the rash on exam, have been described as DM sine dermatitis.¹

Antisynthetase Syndrome (ASyS)

Muscle biopsy will show edema and scattered perimysial CD68⁺, CD4⁺, and CD8⁺ cells.¹

Immune-Mediated Necrotizing Myopathy (IMNM)

Muscle biopsy will show necrotic fibers with scattered distribution in differing stages of necrosis.¹

Inclusion Body Myositis (IBM)

On muscle biopsy, endomysial inflammation, and either invasion of non-necrotic muscle fibers or presence of rimmed vacuoles are seen. Ragged red fibers may also be seen.¹

Polymyositis (PM)

On muscle biopsy, endomysial infiltrates of CD4⁺ and CD8⁺ T cells are seen. Degeneration, necrosis, and regeneration may also be seen.¹

Overlap Myositis

Muscle biopsy shows variable findings, including necrotizing myopathy.¹

Early predictions of outcomes

Patients who are MSA-negative have higher rates of sustained remission than patients who are MSA-positive, particularly in anti-ASR, anti-MDA5, and anti-TIF1 positive patients.⁵ Higher levels of anti-TFN1 are associated with more severe disease activity without cancer and a lower survival rate in cancer-associated myositis.⁴ The presence of extramuscular manifestations affect prognosis of IIMs, with lung involvement, particularly ILD, being one of the most severe. Patients with DM-ILD and CADM-ILD have a worse prognosis than patients with PM-ILD.⁵ Anti-ARS, anti-MDA5, and anti-Ro52 autoantibodies have all been correlated with ILD development.¹ An FVC <50% predicts a much higher six month mortality in patients with positive anti-MDA5.⁴ Poor prognosis has been linked to KL-6 and anti-MDA5 autoantibodies.⁵ Anti-Ro52 has been associated with rapidly progressive ILD, and anti-MDA5 autoantibodies have also been associated with skin ulcers.⁵ Anti-HMGCR positive IMNM is associated with good response to treatment, whereas anti-SRP positive IMNM is not.⁵ Pseudoangioedema is a rare DM manifestation that has been associated with severe disease and poor prognosis.⁹

In juvenile-onset IIM, patients with anti-Mi2 may be more likely to enter drug free remission despite severe findings on muscle biopsy, whereas patients with anti-MDA5 autoantibodies are less likely to be able to come off medications despite less severe changes on muscle biopsy.² A study showed that the presence of active rash (Gottron’s) at 3 months, or nailfold capillary abnormalities and rash at 6 months in juvenile DM, were predictive of a longer time to disease remission.²

Evaluating Proximal Myopathy

Figure 7: Diagnostic algorithm for proximal myopathy. A suggested guide to the clinical assessment of a patient with suspected idiopathic inflammatory myositis (IIM). ANA, antinuclear antibody; ASS, anti-synthetase syndrome (also known as ASyS); CK, creatine kinase; CN1A, cytosolic 5′-nucleotidase 1A; CTD, connective tissue disease; DM, dermatomyositis; dsDNA, double-stranded deoxyribonucleic acid; ENA, extractable nuclear antigens; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; IBM, inclusion body myositis; MRI, magnetic resonance imaging; NAM, necrotizing autoimmune myositis (also known as IMNM); OM, overlap myositis; SRP, signal recognition particle; ULN, upper limit of normal.¹⁰

Environmental

There is some data that has linked smoking with IIM in patients who are either anti-Jo1 antibody and/or HLA-DRB1*03 positive.¹ While there are no clear steps to the prevention of developing an IIM, there are steps that can be taken to prevent disease flares. For example, statin medications and statin-containing foods such as oyster mushrooms, red yeast rice, or Pu-Erh tea should be avoided in patients with anti-HMGCR IMNM. Also, patients with skin manifestations should protect their skin from ultraviolet radiation.¹

Social role and social support system

It’s important for patients diagnosed with IIM to have a strong support system as the nature of the diseases can be challenging and life-threatening.

Professional issues

Health-related quality of life has been shown to be significantly impaired in all subsets of IIM when compared to the general population. Disease activity, disease damage, and chronic disease course have all been associated with poorer quality of life.¹¹

Rehabilitation Management and Treatments

Available or current treatment guidelines

The goal of treatment is to improve patient symptoms for functional levels to return to near baseline and not to interfere with activities of daily living. Management and treatment of IIM is complex and challenging due to the variable presentations and disease courses, as well as its multiorgan and systemic manifestations. There is no comprehensive consensus-driven guidelines or FDA-approved therapies due to the lack of strong clinical evidence.¹ Current evidence exists from retrospective cohort studies for all the treatments except for intravenous immunoglobin (IVIg), rituximab and exercise, for which there are randomized controlled studies. However, there are several therapeutics that are currently undergoing phase II or phase III clinical trials using validated disease classification and outcome measures.¹

Glucocorticoids

Oral glucocorticoids are the first-line or initial treatment in most patients with DM, ASyS, IMNM, or PM, especially for those with ILD and significant muscle weakness.¹ Pulse glucocorticoid therapy with intravenous methylprednisolone is used for patients with severe forms of myositis or extramuscular manifestations. Studies have shown a normalization of muscle enzyme levels and improved muscle strength with the use of glucocorticoids; however, glucocorticoids alone are associated with high flare rates. Of note, chronic use of glucocorticoids should be limited due to the adverse effects and long-term complications.¹

Adrenocorticotropic Hormone

Repository corticotropin injection (RCI) is an FDA-approved therapy for both DM and PM; however, it is only used as a 3^rd line therapy due to lack of data to support its use and high cost. RCI contains adrenocorticotropic hormone and other pro-opiomelanocortin peptides that stimulate melanocortin receptors. It is only approved for use in the USA.¹

Traditional Immunosuppressants

There is limited evidence for the efficacy of traditional immunosuppressants, though they are commonly used in conjunction with glucocorticoids.¹ Clinicians frequently start patients on methotrexate or azathioprine in combination with glucocorticoids as initial therapy for myositis unless there are contraindications. Several retrospective and one prospective open-labeled controlled study supported their use in PM, DM, and juvenile DM for muscle and skin disease. Azathioprine has been shown to be relatively safe in pregnancy and is the preferred therapy for patients with alcohol use, liver disease, or concomitant ILD.¹ Mycophenolate is mainly used as a second line agent, though can be used as a first line agent in patients with moderate to severe myositis in association with ILD. Studies have supported its use in IIM, as well as in refractory DM rashes and with ILD.¹ Cyclosporine and tacrolimus are used as second line agents in patients with refractory myositis with either muscle weakness or associated ILD.^1,5 They are both calcineurin inhibitors that lead to inhibition of T cell activation. Their toxic effects require aggressive monitoring.¹ Cyclosporine is mainly used in severe refractory muscle weakness, rapidly progressive ILD, or systemic vasculitis associated with DM or PM. It may be used in conjunction with rituximab for patients with antisynthetase autoantibody positivity and severe ILD (anti-MDA5). It is associated with a higher risk for infections.¹

Immunoglobins

IVIg has anti-inflammatory and immuno-modulating mechanisms without direct immunosuppressive actions.¹ Previously, it has been used as a second line or third line therapy in combination with or following the failure of glucocorticoids and/or other immunosuppressive drugs.^1,5 It is however, being used more as a first line therapy in IIM, especially for IMNM. It should be considered for severe or refractory muscle inflammation and can be used in refractory skin disease.³ Studies have shown it to be safe and effective for refractory DM with muscle weakness and rash. It can be given safely in combination with other immunosuppressive drugs in the settings of pregnancy, infection, or malignancy.¹ It is expensive and has limited availability in some countries. There is also a subcutaneous form of IgG that is being administered through a pump in the treatment of myositis. Studies have shown that subcutaneous IgG has similar efficacy and provides greater comfort.⁵

Biologic Drugs

Rituximab has been shown in several open-label studies to be safe and efficacious in patients with severe and refractory myositis,^1,5 even in patients with IMNM with anti-SRP autoantibodies (a poor prognostic factor). It works by depleting CD20⁺ B cells.¹ Patients with antisynthetase autoantibodies, anti-Mi2 autoantibodies, and having juvenile DM have been shown to benefit from rituximab. It is being used in myositis associated ILD, especially in ASyS.^1,3 It can also be considered in the treatment of skin disease that has been refractory to glucocorticoids and immunosuppressives.³

Anti-TNF Agents

Studies done on anti-TNF agents (i.e., Etanercept) have had discouraging results, despite TNF being implicated in the pathogenesis of myositis. They are not currently recommended in patients with adult myositis;^1,3 however, they may have a role in the treatment of calcinosis in juvenile DM.

Special Therapeutic Considerations

To date, most of the studies performed on myositis were done on patients with DM or PM, where muscle and/or skin were the primary organs involved. New studies are suggested to look at the benefits of therapy options in the new clinical and serological subtypes that have recently been identified. It is also recommended to look at different organ manifestations (other than muscle and skin) or associated conditions such as ILD or dysphagia.¹

Immune-Mediated Necrotizing Myopathy (IMNM)

Historically, induction therapy for patients with IMNM has consisted of high doses of glucocorticoids used in conjunction with either methotrexate or azathioprine. Some recent case series have suggested a more aggressive approach with the use of rituximab and/or IVIg since the nature of the disease is often refractory.¹ There is also a risk of early muscle atrophy in patients who are anti-SRP positive. High doses of IVIg used as a monotherapy without glucocorticoids may be effective in treating patients with anti-HMGCR autoantibodies.¹

Antisynthetase (ASyS)-Associated ILD

Mycophenolate is used as first line therapy for patients with moderate to severe ILD. Cyclosporine and tacrolimus have been used with success for ILD in ASyS. Rituximab has also shown beneficial in the treatment of myositis associated ILD, especially in ASyS.^1,5

Clinically Amyopathic Dermatomyositis (CADM)

CADM is associated with anti-MDA5 autoantibodies and is characterized by severe cutaneous rashes and often with rapidly progressive ILD without objective muscle weakness. They have a high mortality rate and require aggressive combination immunosuppression as first line therapy, which includes glucocorticoids in conjunction with calcineurin inhibitors as well as cyclophosphamide. Rituximab has been used with or without cyclophosphamide in patients with worsening respiratory status.¹

Inclusion Body Myositis (IBM)

IBM is typically refractory to immunotherapy. Glucocorticoids may be beneficial in the short term for some patients with dysphagia. IVIg may slow disease progression, though its long-term effectiveness is unknown. A phase III clinical trial on rapamycin (sirolimus) is currently ongoing for the treatment of IBM. Exercise is currently the only treatment for IBM that has consistently shown a varied degree of benefit, although the type of exercise program is yet to be determined.¹

Dysphagia

Proximal dysphagia can be severe and life-threatening. Patients with refractory dysphagia should undergo work-up to determine the cause of the dysphagia to help direct management. Glucocorticoids, immunosuppressives, and IVIg have been used for the treatment of dysphagia.^1,5 Botulinum toxin can be used for refractory sialorrhea seen in conjunction with dysphagia.⁵

Calcinosis

Calcinosis is seen in severe DM and has been treated with bisphosphonates, diltiazem, rituximab, IVIg, and sodium thiosulfate with some success.¹

Exercise and Therapy

Muscle function and quality of life have been shown to improve after exercise and therapy. Exercise improves strength and function by activating molecular pathways regulating aerobic capacity, capillary growth, and muscle remodeling, while concomitantly mitigating the inflammatory response in muscles.¹ Exercise has been shown to be safe and efficacious in adults with IIM.^1,3 Exercise can also help with overall wellbeing. Therapy, along with exercise, should be started early with gradual progression based on the individual’s response.¹ Physical therapy should be considered a standard treatment for adult and juvenile myositis. Occupational therapy and speech therapy may be involved as well depending on the present functional deficits.

Pediatric IIM

In pediatric IIM, shorter time to diagnosis is associated with improved disease outcome. First line treatment for most cases consists of a combination of methotrexate and high dose glucocorticoids.³ Dosing for glucocorticoids differ between the adult and pediatric population. For adults, 0.5-1mg/kg/day is recommended; whereas in pediatrics, 1-2mg/kg/day is recommended or intravenous methylprednisolone pulses 30mg/kg/day, maximum of 1g daily.³ Mycophenolate mofetil can be used to improve skin and muscle disease. Rituximab may be used in juvenile-onset IIM, especially in the case of refractory myositis.³ There is insufficient evidence for pharmacological management of IIM-associated ILD in juvenile-onset disease.³ A meta-analysis review done in 2022, found that IVIg and subcutaneous immunoglobin therapy used as an adjunct therapy can improve muscle strength in patients with refractory IIM, especially juvenile DM.¹²

At different disease stages

• First line therapy
  • glucocorticoids
  • methotrexate or azathioprine
  • IVIg
  • exercise and therapy
• Second line therapy
  • combination immunosuppression therapy
  • mycophenolate, tacrolimus, or cyclosporine
  • IVIg
  • exercise and therapy
• Third line therapy
  • rituximab, especially for ASyS and ILD
  • cyclophosphamide, for severe ILD
  • combination of rituximab + cyclophosphamide or cyclophosphamide + tacrolimus/cyclosporine for severe ILD
  • IVIg
  • exercise and therapy  
• Experimental therapy
  • rituximab + cyclophosphamide (ILD)
  • tofacitinib (DM, MDA5 ILD)
  • abatacept
  • anakinra
  • adrenocorticotrophic hormone
  • apremilast (skin)
  • ustekinumab (skin)

Coordination of care

Team approach is important both in outpatient and inpatient settings. Coordination of therapies, other specialty involvement (rheumatology, pulmonology, cardiology, and physiatry), and educating staff, therapists, and family/caregivers regarding exercise regimens at the different stages of the disease, as previously discussed, is crucial.

Patient & family education

The patient and family must be educated about disease pathology, long-term prognosis, and activity limitations. Patients and family members will often require time and emotional help dealing with realistic expectations about outcomes, especially when poor prognostic indicators are present.

Measurement of treatment outcomes

The International Network of Myositis Researchers developed and validated standardized measures to assess disease activity. These are known as core set measures, and were developed for use in clinical trials, though can also be used in clinical practice.^1,5 The core set consists of physician and patient global disease activity as well as extramuscular disease activity on a visual analogue scale. It also includes muscle enzyme analyses, manual muscle testing, and patient-reported health assessment questionnaires. Other secondary outcome measures that have been used include muscle strength (hand-held dynamometry), function (functional index, timed up-and-go, or sit-to-stand), ILD (lung function study), or DM rash (Cutaneous Disease Area and Severity Index [CDASI]).¹ Currently patient-reported outcomes measures are being validated for patients with myositis. MRI and ultrasonography of the muscle can also be used to provide objective outcome measures; as can physical activity monitors. Pain and fatigue have also been considered.¹

IIM affects the patient’s quality of life and may lead to long-term disability. Though it is difficult to assess quality of life in a systemic, validated, and quantifiable fashion since the disease may affect multiple organs. Health-related Quality of Life indices are not validated for IIM.¹ The Myositis Activities Profile (MAP) was created for adult DM and PM specifically, and the McMaster-Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) was adapted for DM and PM. The IBM Functional Rating Scale (IBMFRS) has been validated for IBM. However, it was created on the provider viewpoint and patients have revealed that some of the questions are vague or irrelevant.¹

The Childhood Myositis Assessment Score, Childhood Health Assessment Questionnaire, and Juvenile Dermatomyositis Multidimensional Assessment Report are age-appropriate tools that have been created to assess muscle strength, function, and quality of life in the pediatric population.³

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

• IIM are a group of autoimmune disorders characterized by chronic inflammation of the muscle. They include DM, CADM, ASyS, IMNM, IBM, PM, and overlap myositis. With the discovery of new classifications of IIM, it is believed that PM has been over diagnosed, with most patients now being classified as having IBM, IMNM, or ASyS.
• An IIM can be considered when the patient presents with muscle weakness, most commonly gradual-onset symmetric proximal muscle weakness. Most patients will also have elevated muscle enzymes, with creatine kinase being the most sensitive. Potential extramuscular manifestations include skin involvement, ILD, cardiac involvement, arthralgias, and dysphagia. Features of overlap syndromes may be present. 
• MSAs are present in up to 60% of patients with IIM and they can be help with the diagnosis, management, and prognosis of the IIM subsets.
• Additional diagnostic studies can be done to support a diagnosis of IIM. These include EMG, imaging, muscle biopsy, and skin biopsy.
• Management of IIM can be challenging and depends on the specific subsets of IIM and should be individualized for the specific patient. Initial treatment usually includes glucocorticoids in combination with immunosuppressive therapy.

Cutting Edge/Emerging and Unique Concepts and Practice

Treatment of IIM remains challenging, especially in refractor cases, due to the clinical heterogeneity of the conditions as well as the number of therapeutic target organs. In recent years, researchers have been looking into the use of Janus kinase inhibitors, plasma exchange therapy, and other agents for the treatment of IIM. However, validation and efficacy remain unknown for these treatments.¹³

Gaps in the Evidence-Based Knowledge

There are gaps in our understanding the pathophysiology of IIM that need to be addressed to improve treatment and outcomes. Firstly, a nomenclature of IIM and its subgroups needs to widely be accepted. Future research should focus on more specific targeted therapies based on the subgroups (MSAs). The target of the immune system is likely to vary between the subtypes with different clinical features and different MSAs associated with different HLA-DRB1 alleles.¹ We do not know which patient will respond to which treatment. Immunosuppressives have broad effects on the immune system with a multitude of adverse effects. Biomarkers for treatment response and prognosis are currently lacking. Another area of improvement would be to standardize muscle biopsy assessment, as well as to validate commercially available autoantibody assays.¹ Data is needed to predict treatment response, prognosis, and outcome. The goal would be to customize treatment and personalize medicine for the differing subgroups. Treatment may need to be more aggressive earlier to avoid chronicity and tissue damage.

Index of Abbreviations

IIM – idiopathic inflammatory myopathy
ILD – interstitial lung disease
MSA – myositis-specific autoantibodies
SLE – systemic lupus erythematous
PM – polymyositis
DM – dermatomyositis
ADM – amyopathic dermatomyositis
CADM – clinically amyopathic dermatomyositis
ASyS – antisynthetase syndrome
IMNM – immune-mediated necrotizing myopathy
IBM – inclusion body myositis
tRNA – transfer RNA
HMGCR – 3-hydroxy-3-methylglutaryl-coenzyme A reductase
SRP – signal recognition particle
ANA – anti-nuclear antibody
MDA5 – anti-melanoma differentiation-associated gene 5
TIF1 – anti-transcriptional intermediary factor
NXP2 – anti-nuclear matrix protein 2
SAE – anti-small ubiquitin-like modifier activating enzyme
cN1A or NT5C1A – autoantibodies against cystoscolic 5’-nucleotidase 1A
HSF1 – heat shock factor 1
EMG – electromyography
IVIg – intravenous immunoglobin
RCI – repository corticotropin injection

References

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Author Disclosure

Clarice Sinn, DO, MHA
Nothing to Disclose