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Evaluation and treatment of inflammatory myopathies
  1. A A Amato1,
  2. R J Barohn2
  1. 1
    Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  2. 2
    Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA
  1. Correspondence to Dr A A Amato, Department of Neurology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; aamato{at}partners.org

Abstract

The major types of idiopathic inflammatory myopathy include dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune mediated necrotising myopathy (NM). These myositides appear clinically, histologically and pathogenically distinct. DM, PM and immune mediated NM are responsive to immunosuppressive therapy, in contrast with IBM which is generally refractory to therapy. Greater understanding of the pathogenic bases of these disorders should hopefully lead to better treatment. We need well designed, prospective, double blind, placebo controlled trials in order to determine the best therapeutic options for these different disorders.

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The major types of idiopathic inflammatory myopathy include dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). These myositides appear clinically, histologically and pathogenically distinct (table 1).1 2 3 4 5 A fourth subtype, often classed with PM, is immune mediated necrotising myopathy (NM).6 7 8 9 10 11 NM clinically resembles PM but the muscle biopsy just reveals necrotic muscle fibres with minimal inflammatory cell infiltration. Overlap syndrome refers to those disorders in which DM, PM or NM occur in association with another connective tissue disease. IBM may be associated with Sjogren syndrome but is usually not seen with other connective tissue diseases. One also needs to be aware of an increased risk of cancer in patients with DM, PM and NM.12 13 We have seen a number of patients with NM that developed in the setting of statin use.6 The myopathies did not improve with discontinuation of the statin but only after addition of immunosuppressive therapies.

Table 1

Idiopathic inflammatory myopathies: clinical and laboratory features

DM, PM and NM are usually responsive to immunotherapies. Unfortunately, IBM is typically refractory to these agents. However, patients with IBM benefit from physical, occupational and swallowing therapy. This review will focus on the evaluation and treatment of patients with possible idiopathic inflammatory myopathy. As IBM is discussed in detail in an accompanying review, here we will focus on DM, PM and NM.14

Evaluation

A possible inflammatory myopathy should be considered in any patient presenting with progressive weakness. The most important part of the evaluation is the history and physical examination, as the pattern of muscle involvement helps distinguish the inflammatory myopathies from other neuromuscular conditions and from each other. The serum creatine kinase (CK) level is the most important laboratory test but is not always elevated in DM and IBM. Electromyography (EMG) is usually abnormal in an active myositis but the findings are not specific. Skeletal muscle imaging may be useful in the future but often just reveals non-specific features. However, imaging may guide which muscle to biopsy. In this regard, muscle biopsies are invaluable and extremely helpful in the diagnosis of inflammatory myopathies but only when combined with a good clinical examination.

History and physical examination

PM and NM usually manifest in adult life, while DM can present in childhood or in adulthood. DM, PM and NM typically present with symmetric proximal leg greater than arm weakness. Onset of weakness can be acute over days or more insidious over many months. Other complications include dyspnoea related to interstitial lung disease or ventilatory muscle weakness, dysphagia due to oesophageal or pharyngeal involvement and congestive heart failure or arrhythmia from myocarditis. PM and DM may also be associated with arthralgias with or without arthritis. DM can be associated with vasculopathy of the gut leading to gastrointestinal bleeding. Some patients with DM, PM and overlap syndromes develop Raynaud phenomena.

DM is associated with a characteristic rash which typically accompanies or precedes the onset of muscle weakness.1 2 3 15 16 However, development of the rash may be delayed by months leading to an erroneous diagnosis of PM. Some patients have the characteristic rash but never develop weakness (so-called amyopathic dermatomyositis or dermatomyositis sine myositis).17 The classical skin manifestations include the heliotrope (a purplish discoloration of the eyelids) that is often accompanied by periorbital oedema, Gottron papules (raised erythematous lesions over the knuckles (fig 1), Gottron sign (erythematous rash over the extensor surfaces of the elbows, knuckles, hips, knees and malleoli), V sign (erythematous, macular, sun sensitive rash may appear on the face, neck and anterior chest) and shawl sign (erythematous rash on the back of the neck and posterior aspects of the shoulders). The skin on the hands and fingers may be dried and cracked (mechanic hands). Importantly, periungual telegienctasia may be evident. Subcutaneous calcifications may develop over pressure points (buttocks, knees, elbows) and are more common in children.18 19

Figure 1

Dermatomyositis. Severe erythema and scaling are evident on the dorsum of both hands involving the knuckles (Gottron papules) and interphalangeal regions. The nail beds are also markedly abnormal.

IBM invariably presents in patients over the age of 40 years and is probably the most common myopathy in patients over 50 years of age.1 4 20 21 IBM presents in an insidious fashion with progression over several years before affected patients usually come to medical attention. The pattern of weakness is also usually quite different in IBM compared with almost any other disorder. Approximately two-thirds of patients present with early atrophy and weakness of the flexor forearm muscles leading to weakness of the wrist and finger flexion, particularly the deep finger flexors, along with early quadriceps weakness and atrophy in the legs. The hip girdle and anterior tibial muscles are also affected early in IBM. Dysphagia is very common in IBM and may be the presenting feature as well.

It is important to look for features on clinical examination that might point towards another aetiology of the muscle weakness besides a primary myositis. One should assess for scapular winging, calf hypertrophy or calf atrophy that would point towards a form of muscular dystrophy. We look for action and percussion myotonia of various muscle groups (eg, thenar eminence, brachioradialis) and paramyotonia (particularly of the orbicularis oculi) for possible myotonic myopathies that are frequently mistaken for PM.

Laboratory evaluations

The most sensitive measure of muscle destruction is the serum creatine kinase (CK) level. Other muscle enzymes including aldolase, myoglobin, lactate dehydrogenase, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may also be elevated. Serum CK should be elevated in every patient with PM and NM. However, about 20–30% of patients with DM will have normal serum CKs.15 22 23 The serum CK is normal or only mildly elevated in IBM (usually less than 10-fold above normal).4 20 21 Importantly, serum CK levels do not correlate with the severity of weakness. Rarely, serum aldolase may be elevated while serum CK is still within normal limits, particularly when patients have smouldering disease or heralding a relapse.15 22 23

Erythrocyte sedimentation rate is usually normal or only mildly elevated and is not a reliable indicator of disease severity. Antinuclear antibodies are detected in 24–60% of DM, 16–40% of PM and in as many as 20% of patients with IBM.15 20 22 23 These antibodies in DM and PM should lead to a consideration of an overlap syndrome.

Some patients have so-called “myositis specific antibodies” (MSAs).24 25 26 27 28 29 MSAs include: (1) the cytoplasmic antibodies directed against translational proteins (ie, various t RNA synthetases and the anti-signal recognition particle) and (2) those directed against Mi-2 and Mas antigens. The most common of the antisynthetases is the Jo-1 antibody which is associated with interstitial lung disease and Raynaud phenomena (so-called antisynthetase syndrome). This antibody is demonstrated in as many as 20% of patients with inflammatory myopathy. The other antisynthetases are much less common and are each found in less than 2–3% of inflammatory myopathy patients. Some authorities suggest these antibodies may be useful in prognosis. However, these antibodies have never been studied prospectively with regard to their predictive value. Furthermore, most patients do not have any MSAs and these antibodies have not been demonstrated to be pathogenic themselves and they may just represent an epiphenomenon.

Mi-2 antibodies are found in 15–20% of DM patients. Mi-2 is a 240 kDa nuclear protein of unknown function. Anti-Mi-2 antibodies have been associated with an acute onset, florid rash, good response to therapy and favourable prognosis. However, again, it is not known whether DM patients with Mi-2 antibodies respond differently than DM patients without the antibody.

Antibodies directed against signal recognition particle have been associated with myocarditis and a necrotising myopathy on biopsy.28 29 We have seen two patients however who were erroneously diagnosed with a primary inflammatory myopathy because they had signal recognition particle antibodies. They were resistant to immunotherapy and ended up having genetically confirmed calpainopathies (limb girdle muscular dystrophy 2A).

Skeletal muscle imaging

MRI can demonstrate signal abnormalities in affected muscles secondary to inflammation and oedema or replacement by fibrotic tissue, and may help guide the clinician in regard to what muscle to biopsy (fig 2).30 31 32 Whether or not skeletal muscle imaging adds to a good clinical examination and EMG in defining the pattern of muscle involvement in this regard is not clear. Sometimes an MRI is helpful in the assessment of patients with known myositis, particularly in DM patients who have always had normal serum CK levels, and who become weaker, and in differentiating a flare of the myositis from steroid myopathy.

Figure 2

Skeletal muscle MRI (proton density fat suppression) of the upper arm reveals oedematous signal in the biceps brachii in a patient with myositis.

Electrodiagnostic findings

The characteristic EMG features observed in myositis patients include: (1) increased insertional and spontaneous activity with fibrillation potentials, positive sharp waves and occasionally pseudomyotonic or complex repetitive discharges, (2) small duration, low amplitude, polyphasic motor unit action potentials (MUAPs) and (3) MUAPs which recruit early but at normal frequencies.33 In IBM, there are also often intermixed long duration and sometimes large amplitude polyphasic MUAPs owing to the chronicity of the disease as opposed to a neurogenic process. MUAPs are recruited early; that is, there are many MUAPs firing with very little apparent muscle effort. EMG can assist in assessing the specific muscle to biopsy in patients with only mild weakness. We usually carry out EMG on only one side of the body so that we can biopsy a contralateral muscle that has not been traumatised by the EMG, as this may produce necrosis of muscle fibres and inflammation. EMG can help in the evaluation of patients when it is unclear if they are becoming weaker due to a flare in disease activity or type 2 muscle fibre atrophy from disuse or chronic steroid administration. Abnormal insertional and spontaneous activity is expected in active myositis while isolated type 2 muscle fibre atrophy is not associated with such abnormal activity on EMG.

Histopathology

The characteristic histological feature in DM is perifascicular atrophy (fig 3), although this is a late finding and is not found in perhaps only 50% of adult cases when biopsied early in the course of their illness. Inflammatory infiltrate is composed primarily of macrophages, B cells and CD4+ cells in the perivascular and perimysial regions.34 35 These CD 4+ cells are predominantly plasmacytoid dendritic cells as opposed to T helper cells.36 Importantly, in contrast with PM and IBM (discussed later), invasion of non-necrotic fibres is not prominent. Muscle fibres overexpress type 1 interferon inducible genes and proteins, particularly in the perifascicular regions and can be seen even before the development of perifascicular atrophy (fig 3).36 37 Of note, increased expression of type 1 interferon inducible genes is also evident in peripheral blood and levels appear to correlate with disease activity.38 These observations have led to the hypothesis that DM may be caused by overexpression of type 1 interferon by dendritic cells in the perivascular and perimysial regions and this may be toxic to nearby capillaries and the nearby perifascicular muscle fibres.39

Figure 3

Dermatomyositis. Immunoperoxidase stain reveals the deposition of the interferon α/β inducible protein myxovirus resistance 1 on atrophic perifascicular muscle fibres and on capillaries.

The predominant histological features in PM are variability in fibre size, scattered necrotic and regenerating fibres, and perivascular and endomysial inflammation cell infiltrate consisting mainly of CD8+ T cells and macrophages (fig 4). These inflammatory cells surround and sometimes invade apparently non-necrotic muscle fibres expressing major histocompatibility class 1 antigen.34 35 40 Some have argued that invasion of non-necrotic muscle fibres should be required for the diagnosis of definite PM.5 41 However, invasion of non-necrotic muscle fibres is actually not very common in myositis patients, even those that respond to immunotherapy.42 43 From a pragmatic point of view, invasion of non-necrotic muscle fibres should not be requisite for the clinical diagnosis of PM, and perivascular, perimysial or endomysial inflammation without actual invasion of non-necrotic muscle fibres can suffice for a diagnosis of PM in the proper clinical context.43 44 In this regard, it is important to emphasise that perivascular, perimysial and endomysial inflammatory cell infiltrates are non-specific and can be seen in muscular dystrophies, metabolic myopathies following rhabdomyolysis and IBM. Although B lymphocytes are not common, oligoclonal plasma cells have been appreciated in the endomysium in PM and IBM.45 46 Unlike DM, in which there are many plasmacytoid dendritic cells that function as interferon factories, PM and IBM muscle biopsies have many endomysial myeloid dendritic cells that probably function as antigen presenting cells.47

Figure 4

Polymyositis. Muscle biopsy demonstrates endomysial mononuclear inflammatory cell infiltrate surrounding and invading non-necrotic muscle fibres. Haematoxylin–eosin.

A muscle biopsy must be done on any patient considered to have PM, preferably prior to starting immunosuppressive treatment. It is essential to look for histopathological features that would suggest IBM: rimmed vacuoles, eosinophilic inclusions, ragged red fibres, cytochrome oxidase negative fibres, amyloid inclusions and inclusions on electron microscopy. However, the absence of these findings does not exclude the diagnosis of IBM. Muscle biopsy should be assessed for features that might suggest a muscular dystrophy (eg, limb girdle), proximal myotonic myopathy, congenital myopathy or a metabolic disorder (eg, late onset Pompe disease) that can present like PM.

As the name implies, autoimmune necrotising myopathy is characterised by scattered necrotic muscle fibres.6 7 8 9 10 11 Some might class this myopathy with PM. However, inflammatory cell infiltration is quite scant and localised to necrotic muscle fibres and perhaps around small blood vessels. Capillaries with thickened basement membranes (pipestem capillaries) are found in some but not all cases.11 Deposition of membrane attack complex on small blood vessels and depletion of capillaries might also be appreciated, although not as prominently as seen in DM.11 Also, unlike DM, there is no perifascicular atrophy, perivascular inflammation is sparse and tubuloreticular inclusions in endothelium are not commonly seen on electron microscopy.

The muscle biopsy features of IBM are discussed in detail14 in an accompanying review. In summary, the same features seen in PM are also seen in IBM. However, in addition to endomysial inflammatory cell infiltrates surrounding and invading fibres, IBM muscle biopsies usually reveal fibres with one or more rimmed vacuoles containing amyloidogenic inclusions on Congo red stain. In addition, 15–21 nm tubulofilaments may be evident in the cytoplasm and nuclei in scattered muscle fibres. It is important to emphasise that not all IBM biopsies contain these characteristic IBM features and therefore attention must be paid to the clinical features, else one may make an erroneous diagnosis of PM.4 21 43

Malignancy

There is an increased risk of cancer with the first 2–3 years of diagnosis in adults with DM and to a lesser extent in PM and NM.12 13 15 22 23 Cancer occurs in men and women equally. The clinical severity of rash or muscle weakness does not appear to correlate with the presence or absence of a neoplasm. Treatment of the underlying malignancy sometimes results in improvement of muscle strength. Because of the risk of cancer, we perform a malignancy workup on all adults with DM and PM that include chest, abdominal and pelvic CT scans, mammograms in women, along with breast and pelvic examinations in women. A colonoscopy should be done on all patients over the age of 50 years or in those with gastrointestinal symptoms.

Other evaluations

Because of the associated increased risk of interstitial lung disease in DM and PM patients, particularly those with antisynthetase antibodies (eg, Jo-1), we always order a chest x ray along with pulmonary function testing that includes forced vital capacity and diffusion capacity. A high resolution spiral CT scan of the lungs is a sensitive test that demonstrates the features of interstitial lung disease more clearly and may be done in borderline cases. ECGs are performed on every patient to assess for evidence of myocardial involvement. In patients with symptoms or signs of heart failure, an echocardiogram is in order. Cardiac MRI can also be done to assess for signal changes suggestive of myocarditis, similar to skeletal muscle MRI. Patients with dysphagia should undergo a video fluoroscopy to objectively assess their swallowing.

Treatment

There are only a few published prospective, double-blinded, placebo-controlled trials in the treatment of PM,48 DM,49 and IBM,50 51 52 53 54 although there are several ongoing trials that should be completed shortly. Unlike, DM, PM and NM, the vast majority of IBM patients are poorly responsive to immunotherapy. Despite the lack of “evidenced based medicine” based on published clinical trials, it is clear that various immunotherapies are helpful in DM, PM and NM (table 2). However, we do not know which particular therapies are most beneficial, the doses required to see an effect, the best time to initiate second or third line agents, or if some specific agents are more effective in different types of myositis

Table 2

Immunosuppressive/immunomodulating therapy for inflammatory myopathies

Corticosteroids

Corticosteroids are generally considered the treatment of choice for DM, PM and NM.1 2 22 23 The way to dose corticosteroids has varied and there is no one “right way”. One approach is to start patients on prednisone 0.75–1.5 mg/kg up to 100 mg daily every morning and after 2–4 weeks switch directly to alternate day treatment (ie, 100 mg every other day). Patients with more severe disease may need to be slowly tapered to alternate day dosing over 2–3 months (eg, decrease alternate dose by 10 mg every week until they are on 100 mg every other day). Some patients do not tolerate the swings associated with alternate day therapies and this regimen is also not ideal in those patients with diabetes mellitus given the marked fluctuations in blood glucose that can occur. In fact, the most common approach is starting patients on high dose daily prednisone (eg, 60 mg daily) and maintaining them on a daily dose. There are no studies to indicate which approach is most beneficial and associated with fewer side effects. In patients with severe weakness, we often initiate treatment with a short course of intravenous solumedrol (1 g daily for 3 days) prior to starting oral medications.

Regardless of the specific dosing regimen, patients are followed closely initially, at least every 2–4 weeks. We maintain the high dose prednisone until muscle strength normalises, improvement in strength has reached a plateau or there is at least normalisation of serum CK, which usually takes 3–6 months. Subsequently, we slowly taper the prednisone by 5 mg every 2–3 weeks. Once the dose is reduced to 20 mg every other day, we taper prednisone no faster than 2.5 mg every 2 weeks. The majority of patients with DM, PM and NM improve with prednisone treatment although the response may not be complete. Most patients will need to remain on at least a small dose of prednisone (eg, approximately 10 mg daily or equivalent) or a secondline agent (eg, methotrexate) to remain in sustained remission. When no response is noted after an adequate trial of high dose prednisone, other alternative diagnoses (eg, IBM or an inflammatory muscular dystrophy) should be considered, and repeat muscle biopsy should be done.

There is equipoise regarding when to initiate treatment with secondline agents (eg, methotrexate, azathioprine, mycophenolate or immunoglobulin) as one needs to weigh the increased risks of immunosuppression versus possible benefits (eg, faster improvement, steroid sparing effect). We lean towards starting a secondline agent with corticosteroids in those patients with severe weakness or other organ system involvement (eg, myocarditis, interstitial lung disease) and in those with increased risk of steroid complications (eg, diabetics, patients with osteoporosis or postmenopausal women). If we opt only for prednisone treatment, we would add a secondline agent in those who fail to significantly improve after 2–4 months of treatment or if there is an exacerbation during prednisone treatment.

It is important to monitor serum CK levels but adjustments of prednisone and other immunosuppressive agents should be based on objective clinical examination and not CK levels or the patient’s subjective response. An increasing serum CK can herald a relapse, but without objective clinical deterioration, we would not increase the prednisone dose but rather we would hold the dose or slow the taper. A maintenance dose of prednisone may be required to sustain the clinical response.

Increasing weakness in an individual patient may be due to a relapse of the myositis or type 2 muscle fibre atrophy from disuse or chronic corticosteroids. A steroid myopathy is more likely in a patient with a normal serum CK and an EMG that does not show muscle membrane irritability. In contrast, suspicion of a flare of myositis would be stronger in patients who become weaker during prednisone taper, have increasing serum CK levels and abnormal spontaneous activity on EMG.

Concurrent management

If patients have interstitial lung disease or are on prednisone plus another immunosuppressive agent, we also start Bactrim for pneumocystis prophylaxis. Bactrim does not prevent all opportunistic infections. It is important to aggressively evaluate any patient on chronic immunosuppressive treatment for a possible opportunistic infection.

Dual energy x ray absorptiometry (DEXA) is obtained at baseline and every year while patients are receiving corticosteroids to assess for bone loss. Calcium supplementation (1 g/day) and vitamin D (400 to 800 IU/day) are initiated for prophylaxis against steroid induced osteoporosis. We also treat postmenopausal women with a bisphosphonate for prevention and treatment of osteoporosis. Long term side effects of bisphosphonates are not known, particularly in children, men and young premenopausal women; therefore, we prophylactically treat these individuals only if the dual energy x ray absorptiometry scan is abnormal.

Patients are instructed to start a low sodium, low carbohydrate, high protein diet to prevent excessive weight gain. We record blood pressure at each visit as accelerated hypertension and renal failure may occur, particular in patients with scleroderma or mixed connective tissue disease and overlap myositis.55 Periodic eye examinations for cataracts and glaucoma should be performed. We routinely monitor fasting blood glucose and serum potassium levels while they are on high doses of prednisone. Potassium supplementation may be required if the patient becomes hypokalaemic.

Secondline therapies

These agents are used in patients poorly responsive to prednisone or who relapse during prednisone taper as well as for their potential steroid sparing effect (table 2).1 2 In addition, we initiate a secondline agent at the same time we start prednisone in patients with severe weakness or associated comorbidity (ie, interstitial lung disease, myocarditis), diabetes mellitus (for possible steroid sparing effect) or in the elderly or those with known osteoporosis (again for possible steroid sparing effect), as mentioned previously.

Intravenous immunoglobulin (IVIG)

Several small uncontrolled studies have reported a beneficial response in DM and PM with IVIG. A prospective, double blind, placebo control study of IVIG in 15 patients with DM demonstrated significant clinical improvement with IVIG.49 In support of the clinical observations, repeat biopsies in five of the responsive patients revealed an increase in muscle fibre diameter, increase in the number and decrease in the diameter of capillaries, resolution of complement deposition on capillaries and a reduction in the expression of intercellular adhesion molecule 1 and major histocompatibility class 1 antigens. Whether or not IVIG is effective in PM and NM has not been assessed in a clinical trial although our anecdotal experiences suggest it is beneficial in some patients. There is little evidence that IVIG is effective as a monotherapy, so we generally give it when patients do not respond adequately to corticosteroids and other immunosuppressive agents. IVIG is also a useful additional therapy in patients who have complications from corticosteroids and other immunosuppressive drugs.

We initiate IVIG (2 g/kg) slowly over 2–5 days and repeat infusions at monthly intervals for at least 3 months. Subsequently, we try to decrease or spread out the dose: 2 g/kg every 2 months or 1 g/kg per month. Treatment needs to be individualised. Patients should have their renal function checked, especially those with diabetes mellitus because of a risk of IVIG induced renal failure. Flu-like symptoms—headaches, mylagias, fever, chills, nausea and vomiting—are common and occur in as many as half of all patients. Rash, aseptic meningitis, myocardial infarction and stroke can also complicate IVIG administration.

Methotrexate

There are no prospective, blinded, controlled studies of methotrexate in DM or PM. However, retrospective studies report that the majority of DM and PM patients are responsive to methotrexate.56 57 58 59 60 61 Methotrexate is administered only 1 day a week. We usually begin methotrexate orally at 7.5 mg/week given in three divided doses 12 h apart. The dose is gradually increased by 2.5 mg each week up to 25 mg/week. If there is no improvement after 1 month of 25 mg/week of oral methotrexate, we switch to weekly parenteral (usually subcutaneous) methotrexate and increase the dose by 5 mg every week up to 60 mg/week. The major side effects of methotrexate are alopecia, stomatitis, interstitial lung disease, teratogenicity, oncogenicity, risk of infection, pulmonary fibrosis, along with bone marrow, and renal and liver toxicity. We concomitantly treat all patients with folate or folinic acid.

Because methotrexate can cause pulmonary fibrosis, we typically avoid it in patients with myositis who already have the associated interstitial lung disease and try to avoid its use in patients with Jo-1 antibodies. Pulmonary function tests (forced vital capacity and carbon monoxide transfer factor) should be periodically repeated in patients treated with methotrexate. We monitor the complete blood count (CBC) and liver function tests (LFT)—AST, ALT, bilirubin and gamma-glutamyl transpeptidase (GGT)—every 2 weeks until the patient is on a stable dose of methotrexate, then every 1–3 months. It is important to check GGT as it is the most reliable indicator of hepatic dysfunction because AST and ALT can be elevated from muscle involvement alone.

Azathioprine

Retrospective studies indicate that azathioprine is an effective therapy in DM and PM.21 61 A prospective, double blind study comparing azathioprine (2 mg/kg) in combination with prednisone to placebo plus prednisone found no significant difference in objective improvement at 3 months.48 However, in the open label follow-up period, patients on the combination of azathioprine and prednisone did better than those on prednisone alone and required lower doses of prednisone.62

Prior to beginning azathioprine, we screen patients for thiopurine methyltransferase (TPMT) deficiency. Patients who are heterozygous for a mutation in TPMT may tolerate azathioprine at lower dosages but those who are homozygous for TPMT mutations should not receive drug as they cannot metabolise it and may develop severe bone marrow toxicity. In those patients without TPMT mutations, we begin azathioprine at 50 mg/day in adults and increase by 50 mg every 2 weeks up to 2–3 mg/kg/day. Approximately 12% of patients develop a systemic reaction characterised by fever, abdominal pain, nausea, vomiting and anorexia that requires discontinuation of the drug.63 This systemic reaction generally occurs within the first few weeks of therapy and resolves within a few days of discontinuing the medication. Recurrence of the systemic reaction usually follows restarting azathioprine. Other major side effects of azathioprine are bone marrow suppression, hepatic toxicity, pancreatitis, teratogenicity, oncogenicity and increased risk of infection. Allopurinol should be avoided because combination with azathioprine increases the risk of bone marrow and liver toxicity. A major drawback of azathioprine is that it may take 6–18 months to be effective.

CBCs and LFTs need to be followed closely. We decrease the dose if the white blood count (WBC) falls below 4000/mm3 and hold medication if WBC declines to 2500/mm3 or the absolute neutrophil count falls to 1000/mm3. Leukopenia can develop as early as 1 week or as late as 2 years after initiating azathioprine. It usually reverses within 1 month and it is possible to then rechallenge the patient with azathioprine successfully.63 In addition, we also stop azathioprine if the LFTs increase more than twice baseline values. Again, it is important to assess serum GGT as AST, ALT, lactate dehydrogenase and aldolase levels may be increased from muscle involvement while GGT is only elevated if the liver is involved. Hepatotoxicity generally develops within the first several months of treatment and can take several months to resolve. Patients have been successfully rechallenged with azathioprine after LFTs return to baseline.63

Mycophenolate mofetil

Mycophenylate mofetil also has been noted to be beneficial in some patients with myositis.64 65 66 67 This drug inhibits the proliferation of T and B lymphocytes by blocking purine synthesis in only lymphocytes. The starting dose is 1.0 g twice daily and can be increased to 3 g daily in divided doses if necessary. Because mycophenylate is renally excreted, the dose should be decreased (no more than 1 g/day total dose) in patients with renal insufficiency. A possible benefit of mycophenylate compared with other immunosuppressive agents is the lack of renal or liver toxicity with the drug. Whether or not it is more or less effective than other commonly used agents (eg, methotrexate, azathioprine, IVIG) is not known. We have found mycophenolate to be helpful in some patients but we have seen a number of severe infections as a complication.67 Common side effects include diarrhoea, abdominal discomfort, nausea, peripheral oedema, fever and leukopenia.

Ciclosporin and tacrolimus

Ciclosporin68 69 70 71 72 73 74 75 76and tacrolimus77 78 79 seem to be effective in some patients but the cost and potential side effects have limited their use in most myositis patients. Side effects of ciclosporin and tacrolimus are renal toxicity, hypertension, electrolyte imbalance, gastrointestinal upset, hypertrichosis, gingival hyperplasia, oncogenicity, tremor and risk of infection.

We start ciclosporin at a dose of 3.0–4.0 mg/kg/day in two divided doses and gradually increase to 6.0 mg/kg/day as necessary. The ciclosporin dose should initially be titrated to maintain trough serum ciclosporin levels of 50–200 ng/ml. Blood pressure, electrolytes and renal function, and trough ciclosporin levels need to be monitored closely.

Tacrolimus is started at a dose of 0.1 mg/kg and increased up to 0.2 mg/kg (in two divided doses daily). The dose is titrated to maintain a trough level of 5–15 mg/ml. Blood pressure, electrolytes and renal function need to be monitored closely and doses adjusted should renal insufficiency develop.

Cyclophosphamide

There are a few reports of patients treated with oral and intravenous cyclophosphamide with mixed results.80 81 82 83 84 The major side effects are gastrointestinal upset, bone marrow toxicity, alopecia, haemorrhagic cystitis, teratogenicity, sterilisation, and increased risk of infections and secondary malignancies. Given the increased risks associated with cyclophosphamide, we reserve it for patients refractory to most other modalities. When used, we usually pulse patients with cyclophosphamide at 0.5–1 g intravenously/m2/month for 6–12 months. Cyclophosphamide can be given orally at a dose of 1.0–2.0 mg/kg/day but there may be greater risk of haemorrhagic cystitis. Prehydration with intravenous fluids prior to intravenous treatments and maintaining a high fluid intake (oral or intravenous therapy) are important precautions to help avoid haemorrhagic cystitis. Urinalysis and CBCs are monitored closely (every 1–2 weeks at the onset of therapy and then at least monthly). The dose of cyclophosphamide should be decreased if the WBC decreases below 4000/mm3. Cyclophosphamide is withheld if the WBC declines below 3000/mm3, the absolute neutrophil count falls below 1000/mm3 or if there is evidence of haematuria.

Tumour necrosis factor α blockers

Tumour necrosis factor α blockers (eg, infliximab and etanercept) have proven efficacy in rheumatoid arthritis and other autoimmune disorders. A few small reports suggest that these medications may be effective in PM and DM85 86 87 88 89 90 91 although others have noted a poor response.92 93 A double blind, placebo controlled trial of etanercept in DM is ongoing.

Rituximab

Rituximab is a monoclonal antibody directed against CD20, thereby leading to depletion of B cells. A small series of patients have suggested rituximab may be an effective therapy in DM94 95 and PM.96 A large prospective, double blind, NIH trial is currently underway. There have been warnings from the Food and Drug Administration regarding two patients with systemic lupus erythematosus that developed and died from multifocal progressive leukoencephalopathy. That said, we have increasingly tried rituximab in refractory patients after prednisone and secondline agents such as methotrexate, azathioprine, mycophenolate or IVIG have failed. The dose is 750 mg/m2 (up to 1 g), given once and then repeated in 2 weeks. The course of rituximab is usually repeated every 6–9 months.

Plasmapheresis and leukopheresis

A few small open label series suggested that plasmapheresis or leukopheresis could be useful in treating DM, PM and IBM.97 98 99 However, a controlled trial of 36 patients with DM and PM comparing plasmapheresis, leukopheresis and sham apheresis demonstrated no improvement with either plasmapheresis or leukopheresis over the sham apheresis.100

Total body irradiation

Total body irradiation was also reported by some to be beneficial in refractory DM and PM.101 102 103 However, others have not found total body irradiation to be effective in myositis104 and it may, in fact, be deleterious in IBM.105

Thymectomy

A small number of patients with PM and DM have benefited from thymectomy.106

Other therapies

As our understanding of the pathogenic bases of these myositides increases, hopefully there will be better and more targeted therapies. As noted, recent research has demonstrated increased expression of type 1 interferon inducible genes and proteins which may be toxic, particularly in DM.39 There is a trial underway in patients with DM and PM of a monoclonal antibody that blocks interferon α. Other monoclonal antibodies and small molecules that block various inflammatory pathways and cell markers are also in the development pipeline. IBM is still very frustrating as there is no good medical treatment. We still do not know if IBM is primarily an inflammatory or degenerative disorder. We are not optimistic that studies aimed at reducing β-amyloid accumulation in IBM muscle fibres will have much of an effect as the evidence that IBM is caused by toxic accumulation is scientifically weak.107 108

Physical and occupation therapy along with aerobic exercise programmes help patients retain motor function, improve mobility, prevent contractures that can arise and may help fend off the side effects of corticosteroids (eg, type 2 fibre atrophy, weight gain, osteoporosis). Patients with dysphagia or speech disturbance related to inflammation of oropharyngeal or oesophageal muscles may benefit from speech therapy. Cutting food into smaller pieces, alternating food with sips of liquid and simple manoeuvres such as instructing the patient to tuck their chin when they swallow may suffice. Rare patients may need a feeding tube, at least temporarily. Dysphagia is very common in IBM patients and may be temporarily improved with oesophageal dilatation or cricopharyngeal myotomy.

Summary

DM, PM, immune mediated necrotising myopathy and IBM are clinically, histologically and pathogenically distinct categories of idiopathic inflammatory myopathy. DM, PM and immune mediated necrotising myopathy are responsive to immunosuppressive therapy, in contrast with IBM, which is generally refractory to therapy. Greater understanding of the pathogenic bases of these disorders should hopefully lead to better treatment. We need well designed, prospective, double blind, placebo controlled trials in order to determine the best therapeutic options for these different disorders.

REFERENCES

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Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and Peer review Commissioned; not externally peer reviewed.

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