Inflammatory Myositis

Does this patient have myositis?

The term myositis refers to conditions where there is inflammation of muscle. In practice, myositis tends to be associated with the idiopathic inflammatory myopathies (IMM): polymyositis (PM), dermatomyositis (DM), myositis associated with cancer, juvenile dermatomyositis, overlap myositis, and inclusion body myositis (IBM).

In contrast, myopathy refers to any abnormal condition or disease of muscle, and, by definition, includes myositis. The common clinical features of myositis include weakness, fatigability of muscle, a feeling of exhaustion (asthenia), and sometimes muscle pain (myalgia).

Rheumatologists commonly encounter patients complaining of weakness, fatigue, or muscle pain. While it is true that these symptoms are features of myositis, it is important to remember that the differential diagnosis they suggest is quite extensive. In addition to myositis, the following entities can cause weakness, fatigue, and/or myalgia:

Effects of a toxin/drug.
Neurologic disorders such as myasthenia gravis and amyotrophic lateral sclerosis (ALS).
Endocrine and electrolyte abnormalities.
Infections.
Rheumatologic conditions such as polymyalgia rheumatica and rheumatoid arthritis.
Muscular dystrophies
Metabolic myopathies

Other entities

In addition to the idiopathic inflammatory myopathies, other entities may be associated with inflammation in muscle biopsies such as sarcoidosis, granulomatous myositis, focal myositis, orbital myositis, macrophagic myofasciitis (a myositis associated with aluminum deposition), some muscular dystrophies, viral myositis, and statin myopathy. Therefore, it is important to keep in mind that the presence of inflammation on muscle biopsy does not automatically mean that the patient has one of the idiopathic inflammatory myopathies or even a primary inflammatory condition; inflammation can be secondary to muscle damage.

Inflammatory myopathy will usually present with muscle weakness, elevation of serum muscle enzymes (i.e. CPK, aldolase, AST/ALT, LDH, serum myoglobin), and sometimes will present with myalgia. However, many of the other entities mentioned above can present with similar symptoms and this can make establishing a clear diagnosis difficult despite an adequate work-up. Nevertheless, because inflammatory myopathy can be treated successfully with aggressive immunosuppressive therapy, it is important to try to distinguish inflammatory myopathy from other forms of myopathy.

Key symptoms

Key symptoms associated with inflammatory myopathy include weakness, fatigue, and, less often, myalgia. These symptoms may be present in isolation, or more than one may be present simultaneously. Patients often have difficulty expressing these symptoms, especially when more than one is present. Therefore, when a patient presents with weakness, one of the first questions that the clinician must answer is whether or not the patient is truly weak.

Weakness

The term weakness refers to a reduction of muscle power and is usually tested for on physical exam by pressing on various muscle groups and asking the patient to resist. Elements of the history suggestive of true weakness include difficulty with climbing stairs, difficulty getting up from the toilet or from a low chair, difficulty stepping up onto a curb, difficulty getting up after sitting on the floor or after squatting, difficulty getting objects down from a shelf, difficulty washing or brushing their hair, difficulty opening jars, or difficulty getting juice or milk out of the refrigerator. Weakness may be caused by a primary disorder of muscle, nerve, or the neuromuscular junction.

Both clinicians and patients will often refer to the feeling of exhaustion that accompanies many autoimmune conditions as fatigue. However, the correct term for this symptom is asthenia. Asthenia is a lack of energy that may exist in the absence of true weakness. It is often associated with sleepiness, difficulty concentrating, or depression. This contrasts with true fatigability, which refers to the decreased ability of a muscle to perform repetitive tasks.

The presence of pain, whether in the muscle (myalgia) or in the joints (arthralgia), may further confuse the patient’s ability to assess whether or not they are truly weak. For example, a patient who has osteoarthritis of the knees may have difficulty going up steps and attribute this to weakness.

Manual muscle testing

To assess whether or not the patient has true weakness, manual muscle testing (MMT) is the most commonly used method. The examiner chooses various muscle groups, places the extremity to be tested in a position to resist gravity, and exerts a force opposite to the force generated by the muscle group tested. If the muscle group cannot resist gravity, it is then tested in a position that allows the joint to go through its range of motion without resisting gravity. For example, when testing the arm flexors, flexion at the elbow while the humerus is perpendicular to the floor resists gravity, but when the humerus is supported parallel to the floor, gravity is eliminated.

One caveat to manual muscle testing is that this method varies considerably between examiners. The height and strength of the examiner affects their interpretation of the patient’s strength. In addition, the examiner must consider what would be “normal” strength for each patient. For example, an 80 year old, 120 pound man who watches TV all day would be expected to be weaker than a 38 year old, 130 pound woman who runs marathons. Therefore, it is important to develop a consistent approach of assessing strength.

A commonly used grading system is the British Medical Research Council grading system: 5 indicates normal strength, 4 indicates the ability to range the muscle group against gravity and resist force from the examiner, 3 indicates active movement against gravity but without being able to resist force from the examiner, 2 indicates active movement in a position only with gravity eliminated, 1 indicates trace contraction, 0 indicates no contraction.

At the higher end of the scale, examiners often insert pluses and minuses. For example, 4+ indicates that the patient cannot resist strong force from the examiner, 4 indicates that the patient cannot resist a moderate force, and 4- indicates that the patient cannot resist a weak force. It is in this range that there is the greatest variability between examiners.

When testing a patient’s strength, one hand should be placed just proximal to the joint of the target muscle group to stabilize the joint; the hand that will exert force should be placed just proximal to the next distal joint of the target muscle group. For example, to examine the arm flexors, one hand is placed posteriorly, just proximal to the elbow and one hand is place over the volar aspect of the wrist. When placing the hands for manual muscle testing, it is important to take into consideration regions of joint instability or pain, areas of painful rash, thin skin and regions of calcinosis.

For a complete exam, bilateral proximal and distal muscle groups should be tested (e.g. deltoids, arm flexors, wrist extensors, hip flexors, quadriceps, tibialis anterior, neck flexors). Confounding factors include pain, asthenia, language barriers, and the patient’s motivation and emotional status. Testing for sensory loss and testing reflexes should also be performed as these factors are usually, but not always, spared in patients with myopathy.

If a patient is complaining of weakness or fatigue but has a normal MMT, this may suggest that the patient has asthenia. However, if there is a large size differential between the patient and the examiner, the physician may not be able to pick up some changes in strength. For example, a patient that used to bench press 400 pounds, but can now only bench press 200 pounds would have a significant decrease in strength that may not be picked up on MMT by examiners with a smaller stature.

Timing of weakness

If the patient has true weakness on physical exam, or if the patient provides history that is convincing for true weakness, the timing of the weakness can be an important clue into the differential diagnosis. If a patient complains of weakness that is episodic as opposed to persistent, this may suggest a metabolic myopathy, transient ischemic attacks, myasthenia gravis, electrolyte abnormalities, or periodic paralysis syndromes. Most inflammatory myopathy causes persistent weakness.

Pattern of weakness and other signs

In addition to diseases of muscle, weakness can be caused by disorders of upper motor neurons, lower motor neurons, and the neuromuscular junction. The pattern of weakness may give a clue as to which is affected. Upper motor neurons disease may be associated with hyperreflexia, a positive Babinski’s sign, distal more than proximal weakness or spasticity.

One-sided weakness (hemiparesis) is highly suggestive of upper motor neuron diseases including ischemic stroke, intracranial hemorrhage, or brain or spinal cord tumors. But, it is important to remember that upper motor neuron disease, such as ALS, can also cause weakness in either just one extremity or both arms, both legs, all four extremities. Language or cognitive abnormalities, or cranial nerve abnormalities may be important clues to suggest upper motor neuron disease.

Lower motor neuron disease may be suggested by the presence of hyporeflexia, muscle twitching (fasciculations), distal more than proximal weakness, or rapid muscle atrophy. Weakness in only one extremity is usually caused by lower motor neuron disease such as with compression of a nerve root, peripheral nerve, or nerve plexus. In these cases, the weakness may be accompanied by neuropathic pain or numbness or both. However, lower motor neuron disease, such as multiple sclerosis, can also cause weakness in both arms, both legs, or all four extremities; in these cases, the presence of lower motor neuron signs may help distinguish the etiology.

Myopathy often causes persistent symmetric proximal muscle weakness, sparing the facial muscles. However, there are many exceptions. Intermittent weakness may suggest a disease of the neuromuscular junction such as myasthenia gravis – especially if the patient has facial involvement such as ptosis, diplopia or dysarthria. Involvement of the face and scapular winging suggests facioscapulohumeral dystrophy. In an older patient, asymmetric weakness involving both proximal and distal muscles (such as the finger flexors) may suggest inclusion body myositis.

The physical exam can be used to confirm the presence of weakness and to establish the pattern of weakness. Just as the pattern of joints involved can give insight into the type of arthritis present, the pattern of muscle involvement can give insight into the type of underlying muscle disorder.

The differential diagnosis of weakness is extensive, and the signs and symptoms of inflammatory myopathy have significant overlap with other myopathies. Therefore, there will be times when the diagnosis remains elusive despite a thorough work-up. However, the accurate diagnosis of inflammatory myopathy is essential in order to initiate early and aggressive immunosuppressive therapy. These issues may lead to situations where patients who have non-inflammatory myopathies are treated with immunosuppressives or where patients who have inflammatory myopathies are not treated.

Usually, a careful history and physical exam combined with appropriate diagnostic testing can distinguish among the myopathies. The following entities may be confused with idiopathic inflammatory myopathy.

Endocrine myopathies

Hypo- and hyperthyroidism, hypo- and hyperparathyroidism, Cushing syndrome and acromegaly can all be associated with proximal muscle weakness. Of these, hypothyroidism is the most likely to cause elevated muscle enzymes. Thyroid and parathyroid abnormalities can be easily diagnosed by testing thyroid hormone levels, parathyroid hormone levels, calcium and phosphorus. Weakness associated with Cushing syndrome and acromegaly usually occurs at a time when the other distinguishing clinical features are evident.

Infections

Viruses, bacteria, and parasites all can cause inflammation of muscle. Viruses may induce diffuse weakness, myalgia, or elevated CPK. Those reported to do so include HIV, Coxsackie, rubella, EBV, and hepatitis B. These cases are usually self-limited and associated with other signs and symptoms of infection. Bacterial infections of muscle are often due to staphylococcus or streptococcus, are usually focal, and may be associated with abscess formation (pyomyositis). Trichinosis and toxoplasma can cause a polymyositis-like illness.

These entities may be associated with elevated serum antibodies to the organisms and the organisms may be observed on muscle biopsy.

Toxic myopathies

Statin drugs are a frequent cause of toxic myopathy. Statin myopathy may manifest as myalgia, weakness, elevated muscle enzymes or all three. Severe cases may be associated with rhabdomyolysis. Recently, it has been reported that some patients may have an inflammatory myopathy triggered by the statin. The myopathic effects of the statin drugs appear to be dose dependent, and exercise may worsen symptoms.

When starting a statin, testing CPK is recommended only for those with myopathic symptoms at baseline, patients with renal or hepatic dysfunction or in those patients taking medications known to interact with statins. During therapy, monitoring CPK is recommended only for those presenting with muscle symptoms. Severe symptoms should prompt discontinuation of the drug, while mild symptoms may necessitate close monitoring or lowing of the dose.

In patients who have already been diagnosed with inflammatory myopathy, it is unclear whether lipid lowering agents worsen the condition, however it seems reasonable to avoid use of these agents, if possible.

Many other drugs and toxins can also cause myopathy, including fibric acid derivatives (particularly when used in combination with statins), cimetidine, colchicine, hydroxychloroquine, labetalol, AZT, amiodarone, hydroxyurea, rifampin, phenytoin, corticosteroids, cocaine, heroin and ethanol.

In most cases, stopping the offending agent leads to a resolution of symptoms, but the duration that symptoms remain following withdrawal is variable and may take months. Therefore, it is important to take a detailed history of medication, alcohol and recreational drug use.

Metabolic myopathy

Metabolic myopathies are a large, heterogeneous group of disorders in which patients have genetic defects in the pathways of carbohydrate breakdown (the muscle glycogenoses), in lipid metabolism, or in mitochondrial DNA. These defects affect the ability of skeletal muscle to use energy. The symptoms of these diseases usually begin in childhood or as a young adult but may also occur well into adulthood.

The clinical features of metabolic myopathies may be indistinguishable from idiopathic inflammatory myopathy (progressive, persistent, proximal muscle weakness) but will often present as episodic fatigue, muscle aches or cramps following activity. In addition, muscle enzymes may be elevated and, occasionally, rhabdomyolysis follows strenuous activity.

Examples of the muscle glycogenoses include myophosphorylase deficiency (McArdle’s disease), phosphofructokinase deficiency, acid maltase deficiency, and branching enzyme deficiency. Many other muscle glycogenoses exist although they typically do not cause proximal muscle weakness. Disorders of lipid metabolism include primary carnitine deficiency and carnitine palmitoyltransferase deficiency.

Because these entities may be inherited, patients may report a family history of muscle weakness or fatigability after exercise. Thus, a careful family history can aide in the diagnosis. The forearm lactate-ammonia exercise test may be used to screen for some of the inborn errors of glycogen metabolism but often yields false positive results. Of note, this test does not need to be performed under ischemic conditions as it may precipitate rhabdomyolysis.

Inflammation is not usually observed on MRI of involved muscle group, which can help differentiate from IIM but certainly can be present during a time of muscle injury. Ultimately, muscle biopsy with analysis of the tissue using histochemistry, biochemistry or electron microscopy is the most useful for making the diagnosis of these entities. Blood-spot testing can be used to test for acid maltase deficiency (Pompe’s disease) which is an important consideration as there is now therapy available for this condition.

Muscular dystrophies

The muscular dystrophies are a large group of genetic disorders in which there are mutations in the genes of structural sarcolemmal proteins and glycoproteins. Dystrophin and dysferlin are included in this protein complex, but there are many other associated proteins and glycoproteins which may be mutated and associated with disease states. These disorders include Becker muscular dystrophy, facioscapulohumeral dystrophy, limb-girdle muscular dystrophy, myotonic dystrophies, and the distal myopathies.

Although the clinical presentation may indistinguishable from inflammatory myopathy, clinical features may help distinguish between the two. Muscular dystrophies are associated with presentation in childhood or adolescence, a slowly progressive course, early muscle atrophy, involvement of the facial muscles, a family history of muscle weakness, calf atrophy or hypertrophy, and early distal muscle weakness. In muscle biopsies, abnormal staining for the dystrophin complex can distinguish the muscular dystrophies from other forms of myopathy. Genetic testing is also available for some of the muscular dystrophies, but it is expensive.

Other disorders

Because inflammatory myopathy may, at times, present with muscle pain or tenderness, fibromyalgia and polymyalgia rheumatica may be confused with inflammatory myopathy. The muscle pain and tenderness, which is characteristic of these disorders, may confound the ability to perform accurate manual muscle testing. Because, in fibromyalgia, there is no inflammation and no muscle injury, the ESR, CRP and muscle enzymes should be normal. Although polymyalgia rheumatica is a systemic inflammatory disease and the ESR and CRP are usually elevated, muscle enzymes are normal.

Diseases of the neuromuscular junction including myasthenia gravis and Eaton-Lambert syndrome result from the production of autoantibodies that interfere transmission of signal at the neuromuscular junction. They may present as symmetric proximal muscle weakness, but weakness usually gets worse with repetitive muscle use, facial muscles may be involved, and muscle enzymes are usually normal.

What tests to perform?

Laboratory testing

Initial laboratory work-up for suspected myopathy should include the following:

Thyroid function tests.
Serum muscle enzymes (CPK, aldolase, AST/ALT, LDH, serum myoglobin).
Electrolytes and complete blood count.
Erythrocyte sedimentation rate and C-reactive protein.
Anti-nuclear antibody.

Testing for serum muscle enzymes is an indirect marker of muscle damage. CPK is the most commonly used, but it is not the only one that is useful. Serum CPK may not be elevated in some patients with muscle disease because of decreased muscle mass or the presence of an antibody that binds to the enzyme and interferes with detection. In this situation, the other muscle enzymes may be useful.

Although the AST/ALT are commonly used as markers of liver injury liver, these enzymes also present in muscle and may be released when muscle is injured. This has the potential to cause confusion, and lead the physician to suspect liver damage. Testing the gamma glutamyl transpeptidase (GGT) level, which is specific to liver, can help resolve this question and prevent an unnecessary liver biopsy in a patient with muscle disease. This issue is of particular importance to those patients on known hepatotoxic drugs, such as methotrexate.

Depending upon the assay used, ANA’s have been reported in 60-80% of sera from patients with polymyositis or dermatomyositis. Antibodies directed against tRNA synthetases are present in approximately 20-30% of myositis patients. Anti-Jo-1, an antibody to histidyl-tRNA synthetase, is the most common, occurring in 80% of these anti-synthetase patients. The anti-synthetase antibodies are usually associated with either dermatomyositis or polymyositis but rarely may be found in patients with inclusion body myositis. Clinically the anti-synthetase syndrome is associated with interstitial lung disease, nonerosive arthritis, myositis, fever and Raynaud’s phenomena.

Antibodies directed against the signal recognition particle complex are present in less than 3 % of patients. Anti-SRP antibodies identify a syndrome of severe and rapidly progressive proximal muscle weakness, markedly elevated levels of serum CK, an association with cardiac involvement and poor response to steroid therapy. Anti-Mi-2 antibodies are associated with dermatomyositis that responds well to therapy.

Imaging

EMG can differentiate neuropathic from myopathic causes of weakness in cases where the etiology is unclear. The test involves placing needle electrodes in various muscle groups and measuring the muscle potentials. Myopathies will cause characteristic abnormal potentials, but it is frequently not possible to distinguish between myopathies. The results are operator dependent, and therefore it is important to refer to someone who is experienced with the technique. Also, the test can be quite painful, so it is a good idea to warn the patient beforehand.

MRI is useful in the evaluation of inflammatory myopathy patients. In T1 weighted images, muscle normally has a low to intermediate signal (grey or dark). Scarring and fatty replacement of muscle, which may be seen with in advanced inflammatory myopathy, appears bright. In fat suppressed images, such as short tau inversion recovery (STIR), one can observe edema within muscle, which appears bright. A bright signal within muscle on STIR imaging suggests inflammation or trauma.

Therefore, in the assessment of inflammatory myopathy, MRI is useful in the following ways: as a non-invasive test to determine whether inflammation may be present in a symptomatic muscle group; as a guide to identify a suitable muscle for biopsy; as a monitoring tool to assess whether treatment has been successful (for example, if the clinician is trying to distinguish active inflammation from steroid myopathy); as a way of loosely quantitating how much damage is present in muscle.

Biopsy

In general, muscle biopsies are indicated when muscle disease is suspected based on a thorough history and physical exam. Typical symptoms suggestive of muscle disease include true muscle weakness, fatigability, or pain. Elevated serum muscle enzymes, evidence of myopathy on EMG, and evidence of inflammation on MRI can all help strengthen suspicion of muscle disease.

The choice of muscle to be biopsied is important and is based on the pattern of symptoms. When possible it is preferable to biopsy a muscle that is symptomatic but not so severely involved that the primary process cannot be recognized due to end stage destruction and scarring. For this reason, it is useful to wait approximately 1 month before performing a biopsy in a region of rhabdomyolysis. The selection of muscle to be biopsied can be guided by MRI or ultrasound. Sites where EMG has been performed, sites of injection or trauma should be avoided as these may show inflammation secondary to the traumatic event.

In dermatomyositis, the muscle biopsy commonly shows atrophic muscle fibers observed at the periphery of the fascicle. Also, cellular infiltrates composed of B lymphocytes and CD4 positive T lymphocytes are found in both aperifascicular and perivascular distribution. Complement components and immunoglobulins line the capillary walls, as seen by immunohistochemistry. The capillaries exhibit both a reduction in density and an increase in the lumen diameter of the remaining capillaries, changes thought to lead to secondary muscle ischemia.

In the muscle biopsies of polymyositis patients, cellular infiltrates composed mainly of CD8 positive T lymphocytes can be observed surrounding and invading normal muscle fibers. By immunohistochemistry, myofibers can be seen to express MHC class I on their surface. The T-cell receptor repertoire observed in lymphocytes that have been isolated from the muscles of these patients shows restriction when compared to the lymphocytes of the peripheral circulation; this suggests an antigen-driven, oligoclonal T-cell expansion.

In inclusion body myositis, findings on muscle biopsy may show the presence of vacuolated muscle fibers with basophilic granular deposits, the presence of varying degrees of cellular infiltrate, and the presence of intra-fiber protein aggregates. If these findings are not present, it may be difficult to distinguish from polymyositis.

The protein aggregates observed on biopsy have similarities to those found in Alzheimer’s disease, consisting of either beta amyloid or phosphorylated tau proteins. Ubiquitin, mutant ubiquitin, caveolin, cholesterol, and many enzymes or other proteins involved in the processing and folding of amyloid precursor protein have also been found associated with these intracellular inclusions. This may suggest that abnormalities in protein handling may cause large amounts of misfolded protein to accumulate within and cause damage to muscle fibers, which may then trigger inflammation.

How should patients with inflammatory myositis be managed?

First line therapy

In general, first line therapy includes starting the patient on a high dose of corticosteroid (approximately 1 mg/kg) until there is improvement of strength and a decrease in the levels of muscle enzymes, which takes approximately 4-6 weeks. Then the dose is slowly tapered over months by about 20% per month. Because some patients with inflammatory myopathy have a monocyclic disease course, those who respond well may eventually be tapered off of steroids completely or may be maintained on a low dose.

If the patient has medical co-morbidities that make treatment with corticosteroids difficult or if the patient has severe disease at onset, it is reasonable to start an immunosuppressive, in addition to steroids, at the beginning of treatment. If the patient does not respond well to steroid therapy or if they flare during the taper, the addition of second line therapies and third line therapies can be considered.

During treatment, patients are monitored using a combination of serum muscle enzymes, muscle strength testing, and attention to extra-muscular manifestations of the disease. Of note, the muscle enzymes may return to normal before the patient has either a subjective or objective improvement in strength. In addition, after disease control has been achieved, a rise in muscle enzymes may predict subsequent worsening of clinical status.

If a patient is started on prednisone and has known malabsorption, or if they fail to show cushingoid features after many weeks of high dose prednisone, they may benefit from a change to methylprednisone or dexamethasone. Patients who have a flare of disease during the steroid taper may respond to:

A small increase in the steroid dose followed by a slower steroid taper, or:
A large increase in the steroid dose followed by a rapid taper to a level just above where the patient flared then followed by a slower rate of dose reduction, or:
Intravenous pulse methylprednisone (e.g. 0.5 to 1 g daily for 3 days).

The severity of the flare and the patient’s medical co-morbidities can help guide the clinician as to which approach is most suitable. It has been reported that patients who have mild disease may respond to lower initial doses of corticosteroids, but it is not clear if early initiation of an immunosuppressive agent is required. Patients with overlap syndromes also may need less corticosteroid at initiation of treatment.

Second and third line agents

Immunosuppressive drugs (e.g. methotrexate, azathioprine, cyclosporine, mycophenolate, cyclophosphamide) or intravenous immunoglobulin (IVIG) may be initiated in the following circumstances: when steroid therapy of an appropriate dose and time is not effective; if the patient flares frequently during attempts to reduce the steroids; if steroid-side effects are not tolerated and a “steroid sparing” agent is desired; if the disease is severe and rapidly progressive or life threatening.

In patients who have little or no response to an adequate steroid trial, it is always important to reconsider the diagnosis, possibly performing new diagnostic tests. It is also important to consider that patients who have concomitant malignancy may not respond as expected to therapy. Patients who have the anti-SRP antibody tend to be difficult to treat.

Methotrexate and azathioprine are commonly used second line agents. Methotrexate is usually prescribed at 15-25 mg weekly, given orally, subcutaneously, or intramuscularly. Folic acid or folinic acid is given in addition to the methotrexate to help minimize side-effects.

Azathioprine is typically prescribed at 1.5-2.0 mg/kg/day orally. Cyclosporine is usually started at 2.0-2.5 mg/kg/day and can be slowly increased to a maximum of 5.0 mg/kg/day. Mycophenolate mofetil (MMF) initiated at 250-500 mg twice per day and is escalated every few weeks to 1000 mg twice daily.

IVIG is usually given at a total 2g/kg on a monthly basis. Because a common side effect, aseptic meningitis, appears to be related to the infusion rate, the above dose is often given over 3-4 days at approximately 0.5 g/kg/day. There are many preparations of IVIG that are available, each with a varied amount of salt and sugar content; this may be a consideration in patients with medical co-morbidities. Cyclophosphamide is usually reserved for life threatening disease activity.

What happens to patients with inflammatory myositis?

The inflammatory myopathies share the following common clinical characteristics: muscle weakness (usually symmetric and proximal, sparing the muscles innervated by the cranial nerves), increase in the serum concentration of certain intracellular muscle components such as enzymes (e.g. creatinine kinase) or myoglobin, abnormal electromyogram (EMG), and inflammation seen on muscle biopsy.

The Bohan and Peter classification criteria suggest that a diagnosis of inflammatory myopathy is definite if all four of these elements are present, probable when three are present and possible if two are present. The diagnosis of dermatomyositis has the additional requirement that a characteristic rash be present. These criteria have come under criticism for not being able to distinguish well between inclusion body myositis, polymyositis, toxic myopathy, and certain metabolic and genetic myopathies.

Dermatomyositis and polymyositis present with progressive weakness (worsening over weeks to months). The weakness is usually symmetric and proximal in both the upper and lower extremities, causing difficulty with activities of daily living such as putting items up on shelves, getting up from the toilet, or going up stairs. If distal muscles become involved it is usually late in the course.

Patients with inclusion body myositis are more likely to have a slower progression of weakness, asymmetric muscle involvement, and early involvement of distal muscles groups. Because the proximal portion of the esophagus contains skeletal muscle, patients may also experience dysphagia, a risk factor for aspiration pneumonia.

Because dermatomyositis is often associated with a characteristic rash and because inclusion body myositis often has a characteristic pattern of weakness in an older patient, polymyositis can be the most challenging of the three to differentiate for other causes of myopathy, such as toxic myopathy muscular dystrophies and metabolic myopathies.

Features that can be suggestive of inflammatory myopathy include the following: persistent, symmetric, proximal weakness; lack of early atrophy or hypertrophy; lack of neurologic symptoms; lack of facial involvement; constitutional symptoms; arthritis; positive serologies; hypergammaglobulinemia; response to immunosuppressive drugs.

Characteristic rash

In dermatomyositis, a characteristic rash may appear before the onset of weakness. On occasion, rash may be present with little or no evidence of myopathy (amyopathic or hypomyopathic dermatomyositis).

Characteristic skin manifestations include the following:

Violet discoloration in a periorbital location or on the extremities, (heliotrope or lilac rash); in the periorbital region, swelling is usually present with the rash.
Gottron’s papules: erythematous, raised areas over the bony prominences of the hands, elbows, and knees.
Macular erythema in a V-shape on the chest (V-sign) and over the posterior thorax (shawl-sign).
Mechanic’s hands: cracked areas of skin located on the palms and radial aspects of the fingers.

By routine histological examination, one may observe cells of the monocyte/macrophage lineage and CD4+ T-lymphocytes forming infiltrates arranged in a perivascular distribution in the superficial dermis. The immunohistochemistry of the skin biopsy shows immune complex deposition and evidence of complement activation products at the dermo-epidermal junction.

Pulmonary involvement

Pulmonary involvement is frequent in the inflammatory myopathies and may include aspiration pneumonia (as a result of dysphagia) or hypoventilation due to weakness of the respiratory muscles. Furthermore, bronchiolitis obliterans with organizing pneumonia (BOOP), nonspecific interstitial pneumonia, and interstitial lung disease may all be seen as a consequence of the autoimmune attack on the lung itself.

Interstitial lung disease occurs in approximately 10-50 % of patients with inflammatory myopathies, and is more frequent in patients with auto-antibodies to the tRNA synthetases. Interstitial lung disease may be non-progressive or may follow a progressive course characterized by the presence of opacities seen on high-resolution CT scanning and neutrophilia noted in the bronchoalveolar lavage fluid.

Inclusion body myositis

Inclusion body myositis is the most common type of myopathy in patients after the age of 50. The weakness progresses slowly and, therefore, diagnosis is often delayed by months to years. IBM may be differentiated from the other IIMs clinically by the pattern of muscle involvement- this becomes more evident as the disease progresses. There may be asymmetric involvement of muscle groups with early distal weakness affecting the wrist and finger flexors. Sensory neuropathy may also be present, a finding not usually seen in DM or PM. Also, patients with IBM typically respond poorly to therapy.

Malignancies

Malignancies have been associated with the inflammatory myopathies particularly with dermatomyositis (approximately 25%). The most common concomitant malignancies include solid tumors such as ovarian, lung and gastro-intestinal cancers, but also may include lymphomas.

Myopathy may precede identification of the malignancy by years, therefore age appropriate cancer screening in addition to periodic CT of the chest, abdomen, and pelvis has been suggested at diagnosis and continuing up to 2-3 years from symptom onset. Treatment of the underlying malignancy can lead to resolution of the inflammatory myopathy, although this is not always the case.

Myositis specific antibodies

Several myositis specific antibodies are associated with clinical syndromes. The anti-synthetase syndrome is associated with interstitial lung disease, nonerosive arthritis, myositis, fever and Raynaud’s phenomena. Antibodies directed against the signal recognition particle complex are present in less than 3% of patients.

Anti-SRP antibodies identify a syndrome of severe and rapidly progressive proximal muscle weakness, markedly elevated levels of serum CK, an association with cardiac involvement and poor response to steroid therapy. Anti-Mi-2 antibodies are associated with dermatomyositis that responds well to therapy.

How to utilize team care?

Because high dose-corticosteroids are fist line therapy, the drugs will cause many serious side-effects or worsen pre-existing medical problems. Therefore, numerous medical issues (in addition to the myositis itself) become active simultaneously, requiring the coordination of care and good communication between several healthcare providers. Furthermore, treatment with steroids can cause myopathy, creating a paradox unique to the treatment of IIM.

Although corticosteroids usually work well to control the inflammatory myopathy, the use of high doses for a prolonged period causes numerous side effects. It is likely that patients with diabetes will see a worsening of their glycemic control and may even require insulin. Others may develop new-onset, steroid induced diabetes which may or may not resolve as the steroid dose is reduced. Hypertension may arise or there may be a worsening of pre-existing hypertension requiring that antihypertensives are either initiated or adjusted.

Other common side effects of corticosteroids include weight gain, thinning of the skin, easy bruising, cataracts, glaucoma, insomnia, mood change, difficulty concentrating, and muscle cramping.

The loss of bone density secondary to steroids can begin within weeks of the first dose. Therefore, patients should be started on calcium and vitamin D supplementation immediately, and the use of a bisphosphonate should be considered. In patients on chronic steroids, bone density testing should be performed every year.

Steroid myopathy is a toxic myopathy that can come about on moderate to high doses of corticosteroids. Steroid myopathy does not usually cause an elevation of CPK but can, nevertheless, complicate the clinical picture. For example, if a patient with IIM who has responded to steroids suddenly becomes weaker it may not be clear if the weakness is due to a flare of their illness or due to steroid myopathy. Muscle enzyme levels and MRI may help distinguish. Steroid myopathy usually resolves as the steroids are tapered.

Over the last few decades, literature has suggested that exercise if helpful to patients with inflammatory myopathy, even during flares of illness, and does not lead to flares of disease. Therefore, physical therapy should be used in conjunction with medical therapy.

Are there clinical practice guidelines to inform decision making?

No.

What is the evidence?

Amato, A.A., Griggs, R.C. “Unicorns, dragons, polymyositis, and other mythological beasts”. Neurology. vol. 61. 2003. pp. 288-9.

Amato, A.A., Griggs, R.C. “Treatment of idiopathic inflammatory myopathies”. Current Opinion in Neurology. vol. 16. 2003. pp. 569-75.

Askanas, V, Engel, W.K. “Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloid-beta, misfolded proteins, predisposing genes, and aging”. Current Opinion in Rheumatology. vol. 15. 2003. pp. 737-44.

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