When confronted with a dermatomyositis or polymyositis patient not responding to immunosuppressive treatment, physicians must first ask whether the original diagnosis was correct. In this review, we provide a guide to the clinical features and ancillary tests, which might be helpful in the differential diagnosis of myositis. Particular attention is paid to the role of autoantibody detection, as some of them are not only relatively specific for the disease but also associated with unique clinical features including resistance to treatment. Subsequently, other possible explanations of treatment resistance are listed and a short overview of treatment options for resistant myositis patients is given.
Adult idiopathic inflammatory myopathies (IIMs), commonly referred to as myositis, are a heterogeneous group of disorders of presumed auto-immune aetiology characterised by proximal muscle weakness and non-suppurative inflammation of skeletal muscle. IIMs have been traditionally further divided into polymyositis, dermatomyositis, cancer-associated myositis (CAM) and myositis associated with another connective tissue disease. Sporadic inclusion body myositis (s-IBM) is, despite its differences in clinical presentation and response to therapy, usually grouped with IIMs as well. Other rare forms of myositis have also been described .
Diagnosis of inflammatory myopathy
The most frequently used classification criteria of IIM are those proposed by Bohan and Peter in 1975, which are based on a combination of clinical, electromyographic, laboratory and biopsy findings . A list of conditions that need to be excluded prior to making the diagnosis of IIM was provided by the authors . These criteria have been subjected to criticism mainly due to their low specificity for polymyositis; however, they still remain the standard tool in clinical practice up to this day and, when supported by positive biopsy findings, are considered appropriate for inclusion of patients with inflammatory myopathies into clinical trials by The International Myositis Assessment and Clinical Studies Group (IMACS). The classification s-IBM was not considered in the Bohan and Peter criteria and is usually diagnosed when typical findings are present on muscle biopsy . Relying on Bohan and Peter criteria could lead to erroneous diagnosis of polymyositis in patients with other myopathies associated with inflammatory changes on biopsy. The most frequently misdiagnosed condition is probably s-IBM. An international multidisciplinary collaborative effort to develop new classification criteria for IIMs is currently underway.
Current standard treatment modalities
Management of IIMs is based on pharmacological treatment and physical therapy. Most patients with polymyositis or dermatomyositis respond at least partially, whereas patients with s-IBM have a poor response to immunosuppressive treatment and to physical exercise. Therefore, the following treatment recommendations refer to polymyositis and dermatomyositis; treatment of s-IBM will be discussed separately. The cornerstone of pharmacotherapy of IIM is immunosuppressive treatment. Because very few controlled trials have been reported, most recommendations are based on open studies and case series. Oral glucocorticoids remain the first-line treatment, with initial daily doses between 0.75 and 1mg/kg recommended by most authors. Intravenous (IV) pulses of methylprednisolone (1 g) may be needed in patients with severe disease. Most authors nowadays recommend a combination of glucocorticoids with another immunosuppressive agent. The most often used drugs are methotrexate with a weekly dose of 15–25 mg or azathioprine at 2 mg kg/day. Physical therapy is an integral component of treatment of IIM and should be initiated simultaneously with immunosuppressive drugs . Active disease does not preclude physical activity, but supervision by physical and occupational therapists is essential.
Monitoring of disease activity and muscle performance is a vital part of management. In patients with persisting impairment of muscle performance, it is important to distinguish whether continuing disease activity or muscle damage is the cause. Relying solely on serum levels of creatine kinase (CK) in guiding therapy is not sufficient. IMACS has developed a core set outcome measure for myositis, which includes disease activity, disease damage and health-related quality of life . The disease activity measure includes six variables: physician’s and patient’s rating of overall disease activity, health assessment questionnaire (HAQ), manual muscle test (MMT), serum levels of muscle enzymes (two of the following: CK, lactate dehydrogenase, aldolase, aspartate transaminase (AST), alanine aminotransferase (ALT)) and an extramuscular scoring tool – MDAAT and MYOACT ( ). These tools have been developed for use in clinical trials, but are also useful in daily practice.
Current standard treatment modalities
Management of IIMs is based on pharmacological treatment and physical therapy. Most patients with polymyositis or dermatomyositis respond at least partially, whereas patients with s-IBM have a poor response to immunosuppressive treatment and to physical exercise. Therefore, the following treatment recommendations refer to polymyositis and dermatomyositis; treatment of s-IBM will be discussed separately. The cornerstone of pharmacotherapy of IIM is immunosuppressive treatment. Because very few controlled trials have been reported, most recommendations are based on open studies and case series. Oral glucocorticoids remain the first-line treatment, with initial daily doses between 0.75 and 1mg/kg recommended by most authors. Intravenous (IV) pulses of methylprednisolone (1 g) may be needed in patients with severe disease. Most authors nowadays recommend a combination of glucocorticoids with another immunosuppressive agent. The most often used drugs are methotrexate with a weekly dose of 15–25 mg or azathioprine at 2 mg kg/day. Physical therapy is an integral component of treatment of IIM and should be initiated simultaneously with immunosuppressive drugs . Active disease does not preclude physical activity, but supervision by physical and occupational therapists is essential.
Monitoring of disease activity and muscle performance is a vital part of management. In patients with persisting impairment of muscle performance, it is important to distinguish whether continuing disease activity or muscle damage is the cause. Relying solely on serum levels of creatine kinase (CK) in guiding therapy is not sufficient. IMACS has developed a core set outcome measure for myositis, which includes disease activity, disease damage and health-related quality of life . The disease activity measure includes six variables: physician’s and patient’s rating of overall disease activity, health assessment questionnaire (HAQ), manual muscle test (MMT), serum levels of muscle enzymes (two of the following: CK, lactate dehydrogenase, aldolase, aspartate transaminase (AST), alanine aminotransferase (ALT)) and an extramuscular scoring tool – MDAAT and MYOACT ( ). These tools have been developed for use in clinical trials, but are also useful in daily practice.
Treatment-resistant idiopathic inflammatory myopathy
When confronted with a myositis patient who does not respond to therapy as expected, several possible explanations have to be considered: (1) incorrect diagnosis, (2) insufficient drug dosing or presence of steroid myopathy, (3) muscle weakness due to muscle damage or muscle atrophy rather than persistent disease activity, (4) underlying malignancy (especially in dermatomyositis) and, finally (5) true treatment resistance.
Is the diagnosis correct?
The first question to address in a patient with myositis who does not respond satisfactorily to treatment is whether the diagnosis is correct. IIMs are a rare and a heterogeneous group of disorders with a very broad differential diagnosis ( Table 1 ). Patients with dermatomyositis usually present with skin involvement, which, when typical, is virtually pathognomonic for the disease . Presence of skin changes may precede muscle involvement by months or years. Dermatomyositis may, in some cases, present as a pure skin disease without muscle inflammation (amyopathic form of dermatomyositis) or conversely typical features of dermatomyositis may be found in biopsy obtained from a patient who lacks skin involvement altogether (dermatomyositis sine dermatitis) .
| Toxic myopathies (see Table 3 ) |
| Infections: Trichinellosis, Toxoplasmosis, viruses |
| Endocrine disorders: hypo-, hyperthyroidism, Cushing’s syndrome, acromegaly, hyperparathyroidism, vitamin D deficiency |
| Neurological disorders: amyotrophic lateral sclerosis, spinal muscular atrophy, myasthenia gravis, Lambert-Eaton syndrome, channelopathies |
| Metabolic disorders: Glycogen storage disease: deficiency of: acid maltase (Pompe’s disease), phosphofructokinase, myophosphorylase (McArdle’s syndrome), phosphorylase B kinase, debrancher enzyme; Lipid storage myopathies: deficiency of carnitine palmityltransferase II |
| Muscle dystrophies: limb girdle muscle dystrophy (LGMD): (calpainopathy (LGMD2A), caveolin 3 mutation (LGMD-1C), dysferlinopathy (Miyoshi and LGMD2B), myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy (FSH), Becker muscular dystrophy, female carriers of dystrophinopathy, desminmyopathy |
| Mitochondrial disease |
Polymyositis is the most challenging diagnostic entity since there is no specific sign, symptom or finding, with the possible exception of some autoantibodies, and misdiagnosis is therefore not uncommon. It is worth noting that a partial response to glucocorticoid treatment may occur in patients with muscular dystrophies or other non-inflammatory myopathies; hence, it cannot serve as a proof of auto-immune aetiology of patients’ symptoms. Erroneous glucocorticoid treatment not only exposes patients with other diagnoses to the unnecessary risk of side effects, but in the case of dysferlin deficiency, may lead to irreversible worsening of muscle weakness . In resistant cases, a careful review of history, clinical features and laboratory data is mandatory ( Table 2 ), with a special emphasis on the most valuable piece of the puzzle – muscle biopsy findings. New clinical and laboratory tests and in many cases a re-biopsy are required to confirm or refute the original diagnosis and to assess activity of the disease process.
| Typical skin changes-heliotrope, Gottron’s sign, mechanic’s hands |
| Gradual onset of weakness over weeks to months (longer in s-IBM) |
| Proximal involvement with symmetrical distribution |
| Other connective tissue disease features, e.g. Raynaud’s syndrome, arthritis |
| Interstitial lung disease |
| Autoantibody association |
| Features leading away from a diagnosis of inflammatory myopathy |
| Family history of a similar illness |
| Weakness related to exercise, eating or fasting |
| Neurological signs, fasciculations, myotonia |
| Facial weakness |
| Severe muscle cramping |
| Muscle atrophy early or hypertrophy at any time |
| Creatine kinase level >100 times upper limit of normal |
Patient history
A history of similar involvement in a family member is uncommon in patients with IIM and should raise suspicion of muscular dystrophy (X linked, autosomal recessive or dominant), mitochondrial (maternal inheritance) or metabolic myopathy (mostly autosomal recessive). Patients with IIM frequently have other auto-immune disorders; however, this feature does not help in differentiating polymyositis from s-IBM since the increased frequency has been described in both . The age of onset is also an important consideration with polymyositis being virtually non-existent prior to the age of 18 and s-IBM usually affecting persons over 50.
A number of infections and toxins may cause symptoms similar to IIM; history of toxic exposure, travel to endemic areas or relevant risk factors should be sought. Toxic myopathies are commonly drug induced ( Table 3 ) . The most frequently used drugs in general practice with a potential to cause myopathy are lipid-lowering agents. Some drugs may cause cutaneous lesions resembling dermatomyositis without muscle involvement .
| Pathogenic classification | Drug | Clinical features | Laboratory features | Histopathology |
|---|---|---|---|---|
| Necrotizing myopathy | Cholesterol-lowering agents, Cyclosporine, Labetalol, Propofol, Alcohol | Acute or insidious onset; proximal weakness; myalgias | CK: elevated EMG: fibs, PSW, myotonia (statins, cyclosporine), myopathic MUAP | Necrotic muscle fibers; no inflammatory infiltrate |
| Amphiphilic | Chloroquine, Hydroxychloroquine, Amiodarone | Acute or insidious onset; proximal and distal weakness; myalgias; sensorimotor neuropathy; hypothyroid (amiodarone) | CK: elevated EMG: fibs, PSW, myotonia (chloroquine), myopathic MUAP; NCS: axonal sensorimotor neuropathy | Autophagic vacuoles and inclusions |
| Antimicrotubule | Colchicine, Vincristine | Acute or insidious onset; proximal and distal weakness; myalgias; Sensorimotor neuropathy | CK: normal or elevated EMG: fibs, PSW, myotonia (colchicine), myopathic MUAP NCS: axonal sensorimotor neuropathy | Autophagic vacuoles and inclusions; axonal degeneration |
| Mitochondrial myopathy | Zidovudine | Acute or insidious onset; Proximal weakness; myalgias; rhabdomyolysis; painful sensory neuropathy | CK: normal or elevated EMG: normal or myopathic NCS: axonal sensory neuropathy/neuronopathy | Ragged red fibers, COX-negative fibers; may see inflammatory cell infiltrates, cytoplasmic bodies, nemaline rods |
| Inflammatory myopathy | L-tryptophan, D-penicillamine, Cimetidine, L-dopa, Phenytoin, Lamotrigine, Interferon-α, Hydroxyurea, Imatinib | Acute or insidious onset; proximal weakness; myalgias | CK: elevated EMG: fibs, PSW, myopathic MUAP | Perivascular, perimysial, or endomysial inflammatory cell infiltrates |
| Hypokalemic myopathy | Diuretics, Laxatives, Amphotericin, Toluene abuse, Licorice, Glucocorticoids, Alcohol abuse | Acute proximal or generalized weakness; myalgias | CK: normal or elevated; hypokalemia | Scattered necrotic fibers and vacuoles |
| Unknown | Critical illness myopathy, Glucocorticoids Nondepolarizing neuromucscular blocking agents; Sepsis | Acute generalized weakness including respiratory muscles | CK: normal or elevated EMG: fibs, PSW, myopathic MUAP or no voluntary MUAP NCS: low amplitude CMAP with relatively normal SNAP | Atrophy of muscle fibers, scattered necrotic fibers; absence of myosin thick filaments |
| Omeprazole | Acute or insidious onset; proximal weakness; myalgias; sensorimotor neuropathy | CK: Normal or slightly elevated EMG: myopathic MUAP; NCS: axonal sensorymotor neuropathy | Type II muscle fiber atrophy | |
| Isotretinoin | Acute or insidious onset; proximal weakness; myalgias | CK: normal or slightly elevated | Atrophy of fibers | |
| Finasteride | CK: normal EMG: myopathic MUAP | Variability in fiber size, type II fiber atrophy, increased internalized nuclei | ||
| Emetine | Acute or insidious onset; proximal weakness; myalgias | CK: mild to moderately elevated | Myofibrillar myopathy |
Muscular manifestations
The onset of IIM is typically sub-acute or chronic with predominantly proximal muscle weakness in symmetrical distribution. Facial musculature is usually spared, with the exception of s-IBM. Muscle atrophy may develop after a long duration of illness. Myalgias are not a typical symptom of IIM . The clinical presentation of s-IBM is characterised by slowly progressive muscle weakness, which may be asymmetric. Early selective involvement of quadriceps femoris muscle and flexors of the wrist and fingers causing marked atrophy of these muscles is commonly seen . Sudden onset of muscle weakness, rhabdomyolysis, muscle pain at rest or severe muscle cramps are not typical for IIM and should prompt a search for toxic myopathy or other diagnoses . Muscle pseudohypertrophy or early development of muscle atrophy are characteristic features of muscle dystrophies . Dystrophinopathies usually manifest in children, but patients with Becker dystrophy (incomplete dystrophin deficiency) may develop symptoms in their thirties and female carriers of the Duchenne muscular dystrophy gene may present with muscle weakness in adulthood. Some patients with facioscapulohumeral muscular dystrophy (FSHD) develop symptoms in the fifth decade of life. FSHD may be associated with inflammatory infiltrates in muscle biopsy, but the pattern of muscle weakness with facial involvement differs significantly from that of polymyositis. Limb-girdle muscle dystrophies may also manifest in adults.
IIMs may, in severe cases, affect respiratory muscles. Weakness of respiratory muscles, out of proportion to other muscle groups, causing respiratory failure may be seen in patients with acid maltase deficiency. Myotonia is not a feature of idiopathic inflammatory myopathies and, when present in an adult patient with proximal muscle weakness, should prompt testing for myotonic dystrophy type 2. Visible muscle fasciculations are caused by lower motor neuron involvement and may be seen in patients with amyotrophic lateral sclerosis.
Episodic muscle symptoms, which develop only when the level of physical exertion or state of nutrition requires muscles to rely on the defective pathway, are characteristic of metabolic myopathies. In many such patients, fatigue dominates over true muscle weakness. Development of headache or nausea during the symptomatic episode is highly suggestive of a metabolic disorder. Patients with myophosphorylase deficiency (McArdle’s disease) typically experience an increase in exercise capacity after brief resting – a feature called the second-wind phenomenon. Exercise intolerance accompanied by weakness that is exacerbated by carbohydrate intake (out-of-wind phenomenon) is seen in patients with phosphofructokinase deficiency .
Extramuscular involvement
IIMs are systemic diseases and in some patients (for instance, in patients with antisynthetase syndrome (ASS) ( Table 4 )), extramuscular manifestations can dominate the clinical picture. The pattern of extramuscular involvement may help in formulating the differential diagnosis in treatment-resistant myositis. Presence of general symptoms of inflammation such as fever and fatigue suggests an inflammatory aetiology. Further, interstitial lung disease (ILD) and arthritis, relatively frequently seen in patients with IIM, make other myopathies less likely. Skin manifestations are the defining feature of dermatomyositis. Patients with ASS may present with hyperkeratotic lesions on the palmar or lateral aspects of the digits, which due to their gross appearance are called mechanic’s hands or mechanic’s fingers. Neurologic symptoms may be seen in patients with mitochondrial myopathy or with glycogenoses. Cataracts are a well-known complication of glucocorticoid treatment, but early cataract development may be a symptom of lipid-mitochondrial disease or myotonic dystrophy. Gastrointestinal involvement in IIMs is usually limited to dysphagia, which may cause aspiration pneumonitis. Hepatosplenomegaly and colonic pseudo-obstruction as well as renal involvement may be seen in patients with mitochondrial myopathies. Cardiovascular involvement constitutes a major cause of death in IIM; however, clinically significant cardiac manifestations are relatively rare. Conduction abnormalities, arrhythmias and congestive heart failure presumably due to myocarditis may occur in patients with IIM . Cardiomyopathy may be a manifestation of muscular dystrophy, glycogenosis or mitochondrial myopathy.
| Myositis |
| Interstitial lung disease |
| Arthritis (polyarticular, rheumatoid arthritis-like) |
| Fever |
| Mechanic’s hands |
| Raynaud’s phenomenon |
It is important to realise that, particularly, dermatomyositis is associated with an increased risk of malignancy, which may not be apparent at the time of diagnosis. An age and risk factor appropriate neoplasia screening is recommended for all patients and careful vigilance is needed during the first years of disease duration, especially in older or treatment-resistant patients.
Muscle enzymes
Serum levels of CK are elevated in the vast majority of patients with dermatomyositis or polymyositis at presentation, with values reaching up to 50 times above the upper limit of normal. CK elevation is not specific for IIM and it may also be present in patients with muscular dystrophy, metabolic and mitochondrial myopathies, hypothyroidism and in toxic or drug-induced myopathies. In some IIM patients, CK levels may be normal despite active inflammation. Other commonly evaluated muscle enzymes are lactate dehydrogenase (LDH) and aldolase. LDH may be the most useful enzyme for follow-up of patients with established diagnosis . Presence of myoglobinuria or CK levels higher than 100 times of the upper limit of normal are uncommon in IIM and should point to a different aetiology.
Autoantibodies
Autoantibody testing is a useful tool in the diagnostic work-up, since positive result directs our thinking towards a systemic auto-immune disease. Conversely, a negative autoantibody screening in a polymyositis patient without typical extramuscular involvement should raise suspicion of a possible non-inflammatory myopathy. Some autoantibodies are associated with a particular set of symptoms or organ involvement and may contribute to the assessment of prognosis.
Traditionally, autoantibodies are divided into those that are specific for IIMs and those that are only associated with IIMs and can be found in other diseases, such as systemic lupus erythematosus (SLE), systemic sclerosis or mixed connective tissue disease (MCTD). In past few years, several new myositis-specific autoantibodies have been discovered. Tests for some of these are available routinely, but detection of others is currently restricted to research facilities.
Detection of autoantibodies
Various techniques are employed in the detection of autoantibodies specific for or associated with IIM. Indirect immunofluorescence on HEp-2 cells detects antinuclear and/or anticytoplasmic autoantibodies. These autoantibodies subsequently have to be identified by specific tests, for example, the ELISA technique with purified or recombinant antigens, line or dot-blot immunoassays with spotted autoantigens on the nitrocellulose paper, and immunodiffusion or counterimmunoelectrophoresis. Several of the autoantibodies do not react in these assays and immunoprecipitation of proteins or nucleic acids must be used in their detection. These cumbersome tests are available only in few specialised laboratories. Experience suggests that different routinely available tests differ in their performance with an inclination for false-positive or false-negative results. Performance of a particular test should be verified ideally by comparison with the immunoprecipitation technique. Extra caution is always needed when interpreting results of autoantibody testing related to IIM and a combination of several detection methods may be necessary to detect true positivity.
Antisynthetase antibodies
Presence of one of the antisynthetase antibodies ( Table 5 ) is strongly associated with ASS . Eight autoantibodies to different synthetases have been described so far, of which five are detectable by commercially available assays ( Table 5 ). The most frequent is the anti-histidyl-tRNA synthetase antibody (anti-Jo-1), which is present in 20–25% of IIM . The latest additions are anti-phenylalanyl-tRNA synthetase (anti-Zo) and anti-tyrosyl tRNA synthetase (anti-YRS), both of which have been described in a single case only and were associated with features of ASS . The ASS usually presents sub-acutely, with ILD commonly being the first and/or the leading manifestation which may prevail over muscle involvement. This scenario is particularly more frequent with anti-PL-12, anti-OJ and anti-AsnRS antibodies. Even among patients with anti-Jo-1 antibodies, ILD appears before the presentation of myositis in about one-third of cases . Patients also frequently have symmetrical hand and wrist polyarthritis, which resembles rheumatoid arthritis; however, feet are usually spared. ASS is moderately responsive to therapy and tends to flare after tapering of immunosupressive drugs.
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