Treatment-resistant inflammatory myopathy

Best Practice & Research Clinical Rheumatology 24 (2010) 427–440

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Treatment-resistant inflammatory myopathy Herman F. Mann, Physician a,1, Jiri Vencovsky, Professor a, 2, Ingrid E. Lundberg, Professor b, * a

Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, SE 171 76 Stockholm, Sweden b

Keywords: polymyositis dermatomyositis inclusion body myositis (IBM) treatment-resistant myositis

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. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.

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 [1].

* Corresponding author. Tel.: þ46 8 51776087; Fax: þ46 8 5177 3080. E-mail addresses: [email protected] (H.F. Mann), [email protected] (J. Vencovsky), [email protected] (I.E. Lundberg). 1 Tel.: þ420 234075427; Fax: þ420 224914451. 2 Tel.: þ420 234075340; Fax: þ420 224914451. 1521-6942/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.12.008

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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 [2]. A list of conditions that need to be excluded prior to making the diagnosis of IIM was provided by the authors [2]. 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 [3]. 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 1 mg/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 [4]. 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 [5]. 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 (http://www.niehs.nih. gov/research/resources/collab/imacs/main.cfm). 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

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Table 1 Myositis mimics to be considered in treatment resistant cases. 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

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 [6]. 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) [7]. 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 [8]. 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. 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 Table 2 Features pointing towards a diagnosis of inflammatory myopathy [1]. 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 Adapted from [1] with permission.

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polymyositis from s-IBM since the increased frequency has been described in both [9]. 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) [10]. 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 [11]. 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 [12]. 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 [4]. 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 [10,13]. Muscle pseudohypertrophy or early development of muscle atrophy are characteristic features of muscle dystrophies [8]. 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 [13]. 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

Table 3 Toxic myopathies [10]. Drug

Clinical features

Laboratory features

Histopathology

Necrotizing myopathy

Cholesterol-lowering agents, Cyclosporine, Labetalol, Propofol, Alcohol Chloroquine, Hydroxychloroquine, Amiodarone

Acute or insidious onset; proximal weakness; myalgias

CK: elevated EMG: fibs, PSW, myotonia (statins, cyclosporine), myopathic MUAP CK: elevated EMG: fibs, PSW, myotonia (chloroquine), myopathic MUAP; NCS: axonal sensorimotor neuropathy CK: normal or elevated EMG: fibs, PSW, myotonia (colchicine), myopathic MUAP NCS: axonal sensorimotor neuropathy CK: normal or elevated EMG: normal or myopathic NCS: axonal sensory neuropathy/ neuronopathy CK: elevated EMG: fibs, PSW, myopathic MUAP

Necrotic muscle fibers; no inflammatory infiltrate

Amphiphilic

Acute or insidious onset; proximal and distal weakness; myalgias; sensorimotor neuropathy; hypothyroid (amiodarone) Acute or insidious onset; proximal and distal weakness; myalgias; Sensorimotor neuropathy

Antimicrotubule

Colchicine, Vincristine

Mitochondrial myopathy

Zidovudine

Acute or insidious onset; Proximal weakness; myalgias; rhabdomyolysis; painful sensory neuropathy

Inflammatory myopathy

L-tryptophan, D-penicillamine, Cimetidine, L-dopa, Phenytoin, Lamotrigine, Interferon-a, Hydroxyurea, Imatinib Diuretics, Laxatives, Amphotericin, Toluene abuse, Licorice, Glucocorticoids, Alcohol abuse Critical illness myopathy, Glucocorticoids Nondepolarizing neuromucscular blocking agents; Sepsis

Acute or insidious onset; proximal weakness; myalgias

Hypokalemic myopathy Unknown

Omeprazole

Isotretinoin

Autophagic vacuoles and inclusions; axonal degeneration

Ragged red fibers, COX-negative fibers; may see inflammatory cell infiltrates, cytoplasmic bodies, nemaline rods Perivascular, perimysial, or endomysial inflammatory cell infiltrates

Acute proximal or generalized weakness; myalgias

CK: normal or elevated; hypokalemia

Scattered necrotic fibers and vacuoles

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 CK: Normal or slightly elevated EMG: myopathic MUAP; NCS: axonal sensorymotor neuropathy CK: normal or slightly elevated

Atrophy of muscle fibers, scattered necrotic fibers; absence of myosin thick filaments

Acute or insidious onset; proximal weakness; myalgias; sensorimotor neuropathy Acute or insidious onset; proximal weakness; myalgias

Finasteride

Emetine

Autophagic vacuoles and inclusions

CK: normal EMG: myopathic MUAP Acute or insidious onset; proximal weakness; myalgias

CK: mild to moderately elevated

Type II muscle fiber atrophy

Atrophy of fibers

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Pathogenic classification

Variability in fiber size, type II fiber atrophy, increased internalized nuclei Myofibrillar myopathy

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Abbreviations: fibs, fibrillation potentials; NCS, nerve conduction studies; PSW, positive sharp waves; MUAP, motor unit action potential; CMAP, compound motor action potential; SNAP, sensory nerve action potential. Adapted from [10] with permission.

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Table 4 Clinical Features of Antisynthetase Syndrome (ASS). Myositis Interstitial lung disease Arthritis (polyarticular, rheumatoid arthritis-like) Fever Mechanic’s hands Raynaud’s phenomenon

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 [14]. Cardiomyopathy may be a manifestation of muscular dystrophy, glycogenosis or mitochondrial myopathy. 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 [15]. 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 myositisspecific 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

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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 [16]. 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 [17]. The latest additions are anti-phenylalanyltRNA 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 [18,19]. 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 [20]. 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. Serum levels of anti-Jo-1 antibodies correlate to some degree with disease activity [21]. It is not yet clear whether this can be clinically useful. Anti-Jo-1 autoantibodies are fairly specific for polymyositis and dermatomyositis, although they were detected in few patients with s-IBM in one laboratory [17] and therefore, their presence does not exclude this diagnostic entity. Anti-signal recognition particle (SRP) Anti-signal recognition particle (SRP) antibody-positive patients are usually more resistant to glucocorticoid and immunosuppressive treatment compared with others with polymyositis. Anti-SRP autoantibodies are mostly found in patients with polymyositis, although occasional patients with systemic sclerosis or with ASS have been reported [22]. Patients with anti-SRP antibodies usually have Table 5 Myositis specific autoantibodies. Name

Antigen

IIF type

Approximate frequency in myositis

Clinical associations

Anti-Jo-1 Anti-PL-7 Anti-PL-12 Anti-EJ Anti-OJ Anti-AsnRS (Anti-KS) Anti-YRS (Anti-Ha) Anti-Zo Anti-SRP

Histidyl-tRNA synthetase Threonyl-tRNA synthetase Alanyl-tRNA synthetase Glycyl-tRNA synthetase Isoleucyl-tRNA synthetase Asparaginyl-tRNA synthetase Tyrosyl-tRNA synthetase Phenylalanyl-tRNA synthetase Signal recognition particle

C C C C C C C C C

15–30% <5% <5% <5% <5% Rare Rare Single case 4–6%

Anti-Mi-2

NuRD

N

4–18%

Anti-p155/140

155 kD, 140 kD (K562)

N, speckled

13–30%

Anti-CADM-140

RNA helicase encoded by MDA-5 SAE Nuclear matrix protein (NXP-2)

C

19% of DM

ASS ASS ASS ASS ASS ILD þ arthritis. DM ASS ASS Severe PM, necrotizing myopathy Mainly DM, relatively mild disease DM, JDM, particularly CAM C-ADM (ILD)

N, fine speckled N, weakly positive or negative

4% (8% in DM) 23% of JDM

Severe skin in DM, ILD JDM, calcinosis

Anti-SAE Anti-p140 (Anti-MJ)

PM – polymyositis, DM – dermatomyositis, JDM – juvenile dermatomyositis, ASS – antisynthetase syndrome, IIF – type of fluorescence using indirect immunofluorescence method, C – cytoplasmic, N – nuclear, ILD – interstitial lung disease, C-ADM – clinically amyopathic dermatomyositis, NuRD – nucleosome remodeling and histone deacetylase complex, SAE – Small ubiquitin-like modifier activating enzyme, MDA-5 – melanoma differentiation-associated gene 5.

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severe muscle weakness and muscle atrophy with a disability developing rapidly over a period of months [23]. Dysphagia is a prominent symptom. Initial description of frequent cardiac involvement was not confirmed in subsequent studies [22]. ILD is present in almost one-quarter of patients. Serum CK is usually very high and muscle biopsies show little or no endomysial inflammation with frequent necrotic fibres [22,23]. Anti-Mi-2 Patients with anti-Mi-2 antibody positivity typically respond well to treatment. These patients often have a classic dermatomyositis, with cutaneous manifestations including Gottron’s signs or papules, heliotrope rashes, V and shawl rashes and cuticular changes. Although anti-Mi-2 antibodies are typically associated with dermatomyositis, they are only present in some dermatomyositis patients. Furthermore, depending on the test applied, they also have been detected in occasional cases of polymyositis and even s-IBM when an enzyme-liked immunosorbent assay (ELISA) test for anti-Mi-2 fragments was used [24]. Anti-polymyositis/scleroderma (PM/Scl) Patients with anti-polymyositis/scleroderma (PM/Scl) antibodies have myositis or scleroderma, mostly with limited cutaneous involvement. Clinical signs of both conditions are seen in 50–70% of patients with anti-PM/Scl, and 24% of patients with this overlap syndrome have anti-PM/Scl autoantibodies. Besides the association with myositis and/or scleroderma, higher frequencies of Raynaud’s phenomenon, arthritis/arthralgia, ILD, Sjo¨gren’s syndrome, dysphagia and calcinosis have been described [25]. Pulmonary involvement is less severe than in ASS and patients usually have good prognosis [25]. Anti-PM/Scl are directed predominantly against two molecules of 100 kDa (100%) and 75 kDa (60%). Recently, a sensitive ELISA directed at major alpha helical PM/Scl-100 epitope (PM-1) was described with positivity in 55% of patients with polymyositis/scleroderma overlap, in 7.5% of polymyositis and 7.9% of scleroderma patients. Anti-Ku Myositis patients with anti-Ku antibodies are usually responsive to glucocorticoids and have a good prognosis. Anti-Ku may also be detected in other connective tissue diseases [26]. There is a large variation in detection frequencies, which seem to be dependent on the methods employed. The most frequent clinical features observed in these patients are lung involvement, myositis, Raynaud’s phenomenon, sicca syndrome and sclerodactyly [26]. Anti-U1snRNP Patients with anti-U1 small nuclear ribonucleoprotein (U1snRNP) antibodies usually have myositis either as a part of MCTD or as an overlap with SLE or scleroderma. Myositis is often glucocorticoid responsive and is frequently associated with other symptoms such as polyarthritis, Raynaud’s phenomenon, sclerodactyly and fibrosing alveolitis. Novel autoantibodies in myositis There have been several new autoantibodies described in the past 3 years that are specific for myositis. Interestingly, most of them are linked to dermatomyositis and some specific clinical symptoms related to each of these antibodies have been reported. Anti-p155/140 (anti-transcriptional intermediary factor 1-g (TIF1-g)) Anti-p155/140 antibodies were described almost simultaneously by two groups in patients with adult [27,28] and juvenile [27] dermatomyositis (JDM). The detection of this autoantibody is currently possible only by radioactive immunoprecipitation and this fact explains why it was not described sooner, despite its nuclear speckled fluorescence on Hep-2 cells. Anti-p155/140 is probably the second most frequently detected autoantibody in adult myositis after Jo-1 and the most frequent in JDM. In fact, it was found in 29% [27] or 23% [28] of JDM patients, in which it is associated with increased

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frequency of skin lesions [29]. The antibody is specific for dermatomyositis and strongly associated with malignancy in adults. The fact that cancer association is rare in patients with defined antisynthetase and other myositisspecific and associated antibodies led Chinoy [30] to calculate the probability of CAM in patients who are positive for such an antibody and, at the same time, negative for anti-p155/140. This combined strategy yielded almost 100% sensitivity and negative predictive value, effectively ruling out malignancy. The target for anti-p155/140 antibody has recently been identified as transcriptional intermediary factor (TIF1-g). This autoantibody might therefore prove useful in the diagnostic work-up of myositis patients and it may also help in detecting underlying malignancy in dermatomyositis patients that do not respond to treatment. Unfortunately, testing for anti-p155/140 is currently limited to research laboratories. Anti-p140 Another autoantibody reacting with 140 kDa protein (anti-p140), which is distinct from anti-p155/ 140, has recently been described in 23% of patients with JDM [31]. This antibody was detected exclusively in JDM and not in patients with JDM-overlap syndrome or control subjects. None of the anti-p140 antibody-positive patients had any other recognised autoantibody. Immunodepletion studies suggested that the identity of p140 was consistent with nuclear matrix protein (NXP-2) and was identical to previously identified MJ autoantigen. Anti-p140-positive cases were significantly associated with the presence of subcutaneous calcinosis [31]. Anti-CADM-140 Amyopathic dermatomyositis is diagnosed when only typical cutaneous signs are found and no muscle symptoms appear for more than 2 years. If only subclinical muscle involvement is present, a term hypomyopathic dermatomyositis is used. These two subgroups are referred to as clinically amyopathic dermatomyositis (C-ADM). In 53% of these patients, a new autoantibody called anti-CADM140 was detected [32]. High frequency of rapidly progressive ILD was found in anti-CADM-140 positive patients [32]. This autoantibody is very specific for C-ADM and so far has been found only in Japanese patients with C-ADM and in one patient with classical dermatomyositis (DM). The antigen for antiCADM-140 antibodies was identified as ribonucleic acid (RNA) helicase encoded by melanoma differentiation-associated gene 5 (MDA-5) [33]. Recently, an ELISA for detection of anti-CADM-140 antibody was developed and showed a very good specificity and slightly lower sensitivity in comparison with immunoprecipitation [33]. Using this ELISA, the frequency of anti-CADM-140 antibody was detected in C-ADM patients, with rapidly progressive ILD, in significantly higher proportions than in those without it (82% vs. 3%). Routine detection of anti-CADM-140 antibodies has therefore potentially significant clinical implications in geographical areas where these antibodies have been detected so far (Japan and eastern Asia). Rapidly progressive ILD associated with C-ADM is usually not seen in non-Asian patients [33]. Anti-SAE Antibodies directed to small ubiquitin-like modifier 1 (SUMO-1) activating enzymes subunits A and B (SAE) have been initially identified in two patients with amyopathic dermatomyositis, who after several months progressed to proximal myositis. The same group then investigated a large cohort of patients and found this antibody in 8.4% of dermatomyositis patients [34]. The majority of patients presented initially with typical cutaneous disease and progressed to myositis in the median of 3 months. More than 75% of patients had dysphagia and more than 80% had systemic features as defined by fever, weight loss and raised inflammatory markers. Mild ILD was found in only two patients (18%). A strong association with HLA-DRB1*04-DQA1*03-DQB1*03 haplotype was identified.

Anti-200/100 kDa proteins A novel autoantibody specificity which immunoprecipitate a pair of proteins with molecular weights of 100 kDa and 200 kDa was recently described in a case series of patients who had

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predominant necrotic features in the absence of substantial inflammation on muscle biopsy [35]. Patients had variable clinical phenotype and were previously considered to be ‘autoantibody negative’. Magnetic resonance imaging Magnetic resonance imaging (MRI) of muscles can be helpful in evaluating treatment-resistant myositis patients since it can distinguish persisting active inflammation from muscle damage and fatty replacement [36]. The two inherent advantages of MRI are its ability to examine large areas of muscle tissue and its non-invasive nature, making it possible to assess distribution of involvement and to perform repeat studies in a single patient. MRI may also be used to locate an area of active disease, thus increasing diagnostic yield of muscle biopsy [37]. Muscle oedema may be detectable only with MRI-short tau inversion recovery (STIR) technique or with fat-suppressed T2-weighted images. Using gadolinium enhancement increases sensitivity of MRIs for detection of oedema. A finding of muscle oedema on MRI is almost always due to increased water content in the tissue; however, this finding is not specific for inflammation as it may also be seen in patients with other pathologies and injuries. Muscle oedema on MRI may be seen transiently following muscle exercise [38]. In patients with s-IBM, demonstration of characteristic distribution of muscle involvement affecting the quadriceps femoris, medial gastrocnemius and forearm flexors by MRI may help to establish the diagnosis [3]. Muscle biopsy Muscle biopsy is the most important test used in the diagnosis of IIM and, at the same time, it is the most common source of diagnostic errors. In treatment-resistant cases, repeating of muscle biopsy should be strongly considered because histologic changes may be distributed unevenly and therefore, may have been missed in the first biopsy and because some specific findings of s-IBM may develop over time. If a skilled pathologist or the capability to perform some of the studies required (e.g. enzyme histochemistry) is not available locally, a referral to a specialised centre is recommended. Muscle biopsy has a false-negative rate of up to 25% mainly due to uneven distribution of inflammation of muscle tissue in idiopathic inflammatory myopathies [1]. The ideal target for biopsy is a moderately involved muscle, according to muscle testing and/or electromyography (EMG) and MRI. The site injured by EMG electrode placement should be avoided. Biopsy specimen handling and preparation are of outmost importance to ensure a good yield of the biopsy. The biopsy specimen should be frozen, because paraffin embedding renders detection of red-rimmed vacuoles, characteristic of s-IBM, impossible. Frozen specimens are also required for biochemistry and immunohistochemistry analyses. Presence of inflammatory cell infiltrates on biopsy is supportive of but not specific for the diagnosis of IIM since it may occur in patients with various dystrophies, myasthenia gravis or drug-induced myopathies as well [39]. Diffuse major histocompatibility complex (MHC) class I expression, absent in normal muscle tissue, is demonstrable in most patients with IIM. It may also be present in areas without inflammatory infiltrate or in patients who are in a long-term drug-induced remission. In a review of 224 muscle biopsies obtained from patients with various muscle disorders and from normal controls, sarcolemmal MHC I expression was absent in patients with metabolic or congenital myopathies and with neurologic disorders [40]. However, the MHC class I expression on muscle fibres is not specific for IIM since it may be present in patients with dystrophies [40,41]. Invasion of normal appearing muscle fibres by CD8-positive T cells and macrophages along with diffuse MHC-I expression on the surface of muscle fibres is seen in polymyositis and s-IBM. The presence of red-rimmed vacuoles and congophilic inclusions of amyloid protein supports a diagnosis of s-IBM. Electron microscopy is used in s-IBM to detect characteristic 15- to 20-nm cytoplasmic and intranuclear tubulofilaments [39]. Perifascicular atrophy of muscle fibres is a typical feature of dermatomyositis and may be seen even in the absence of inflammatory infiltrate. Other findings that support a diagnosis of dermatomyositis are reduction of capillaries, signs of ischaemia and inflammatory infiltrates in perivascular distribution. Necrotic myopathy is usually paraneoplastic or toxic in origin; however, it may be present in patients with polymyositis associated with certain autoantibodies. Biopsy in these patients may lack inflammatory infiltrate and diffuse MHC I expression on muscle fibres, making the diagnosis difficult [23,35].

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A common mistake in diagnosis of polymyositis is ascribing the lack of inflammatory infiltrate in biopsy to the effect of previous immunosupressive treatment. A course of treatment shorter than 4 weeks does not significantly affect the biopsy findings and diffuse human leucocyte antigen (HLA-I) expression is usually present even after long-term successful therapy [42]. Are there other explanations for insufficient treatment response? Once the diagnosis of IIM has been re-confirmed beyond reasonable doubt and alternative diagnoses have been refuted, the physician must review whether there are other explanations for the lack of therapeutic effect Some patients who do not respond to glucocorticoids have been treated with inadequate doses and/or for an insufficient length of time. The possibility of steroid-induced myopathy, manifesting usually as a deterioration of muscle strength without elevated CK levels after initial improvement also has to be considered. Co-existing pathologies unrelated to inflammatory myopathy have to be excluded. There is clearly an increased risk of malignancy in adult patients with dermatomyositis [43] and aggressive search for occult malignancies is indicated in resistant cases. Cancerassociated myositis usually improves with treatment of the neoplasia, but the overall prognosis depends on the type, stage and grade of the tumour. There are data suggesting that response to treatment is better in dermatomyositis compared with polymyositis and that autoantibody-defined polymyositis groups differ in their response to treatment, with anti-SRP-positive patients being the most treatment resistant. As mentioned previously, the s-IBM usually does not respond to immunosuppressive treatment. There are individuals with disease which resembles s-IBM clinically but who do not have the characteristic changes required for diagnosis even on repeated muscle biopsy. These patients should, for the practical purposes, be considered as having s-IBM. Treatment options in patients who do not respond to conventional immunosuppressive treatment Pharmacotherapy In true refractory polymyositis or dermatomyositis cases, a combination of methotrexate and azathioprine could be considered [44]. Other alternative pharmacological treatment modality is the use of high doses of intravenous immunoglobulins (IVIGs), which had beneficial effects over placebo in refractory dermatomyositis cases in one placebo-controlled trial [45]. However, this effect could not be reproduced in a later open trial of patients with dermatomyositis, polymyositis and s-IBM, where occasional responders were found in either myositis subset [46]. Other drugs that have been reported effective in refractory cases are cyclosporine A and mycophenolate mofetil [47]. Clinical experience suggests that a combination of methotrexate with cyclosporine A may be efficacious in some patients. Cyclophosphamide is usually reserved for treatment of associated ILD, whereas the data on the effects on muscle performance are conflicting [48]. Tacrolimus has been used in patients with ASS with success [49]. Of the new biologic agents, the B-cell-blocking agent rituximab has been reported to be effective in several treatment-resistant dermatomyositis and polymyositis cases and case series [50], but results were less encouraging in other reports. Rituximab in combination with plasma exchange was effective in the treatment of two patients with anti-SRP positive myositis [51]. A currently ongoing placebocontrolled trial of rituximab in myositis may clarify the therapeutic potential of this agent. There are conflicting reports regarding the effects of tumour necrosis factor (TNF) blockade in refractory cases, mostly with negative results. Anakinra, interleukin (IL)-1 blockade was reported with successful outcome in one patient with anti-Jo-1 antibodies and ILD, but this needs to be confirmed in larger trials [52]. There is clearly continuing need for improved treatment options for patients resistant to treatment with glucocorticoids and methotrexate or azathioprine. Physical therapy Muscle weakness and muscle fatigue are common clinical features of IIMs. The aetiology of muscle impairment is multifactorial and still needs to be clarified but one component is a loss of muscle mass,

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which could be induced by several different mechanisms in these disorders: immune-mediated muscle fibre damage, physical inactivity or adverse effects of glucocorticoid treatment. Physical exercise is important to counteract these negative effects of disease and treatment and to regain muscle mass. This could safely be introduced in combination with immunosuppressive treatment and should be guided by physical and occupational therapists [53].

Treatment of sporadic inclusion body myositis The s-IBM patients may respond transiently to immunosuppressive treatment, but overall, the treatment options are disappointing. There is a clear need for increased understanding of disease mechanisms to develop new therapies for s-IBM [3]. In a recent proof-of-principle study, disease progression had been slowed after one series of alemtuzumab infusions [54]. Summary In brief, inflammatory myopathies are a heterogenous group of relatively rare disorders with diverse clinical manifestations and varying response to therapy. Resistant cases are particularly challenging to the clinician since there is always a possibility of misdiagnosis and because data regarding efficacy of various treatment strategies are scarce. Several novel autoantibodies have been described recently, which might be helpful in making the diagnosis and estimating prognosis of patients with myositis. Persisting muscle weakness could be explained by loss of muscle or steroid myopathy rather than persisting inflammation. Finally, better understanding of disease mechanisms is clearly needed to develop new therapies, which then have to be tested in prospective controlled multicentric trials. One of the most exciting developments in the past few years is the growing international collaboration aiming at precisely these goals.

Practice points  When treatment-resistant inflammatory myopathy presents, reconsider the original diagnosis;  When in doubt repeat muscle biopsy;  Some autoantibodies are specific for myositis and/or have important clinical associations;  Distinguish between disease activity and damage; and  Rule out underlying malignancy.

Research agenda    

New validated classification criteria for myositis; Reliable tests for autoantibody detection to be available routinely; New biomarkers associated with diagnosis a prognosis; and Prospective multicentre controlled trials for resistant cases.

Conflict of interest None of the authors has any conflict of interest.

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