There is no clear guidance as to how frequently patients should be screened. However, parti cular vigilance with annual reassessment is advisable for the \201 rst 3 years, especiall y in older people. Needle EMG findings include myopathic potentials visible as low-amplitude, short duration p olyphasic units on voluntary activation, and increased spontaneous activity manifest as \201 brillations, positive sharp waves, and complex repetitive discharges. Several muscles should be examined with EMG including the proximal limb and paraspinal muscles as these giv e the greatest diagnostic yield, and may be the only muscles affected. Differential diagnosis Inclusion body myositis (see also p. 302) \200 Onset of weakness i s more gradual. \200 Has a propensity for involvement of quadriceps and forearm \202 ex ors. Inherited muscular dystrophies \200 Assessment of respiratory muscle function In the acute setting, if respiratory compromise i s suspected, vital capacity should be monitored. Arterial oxygen and carbon dioxide levels may be misleadingly normal. A vital capacity of less than 15 ml/kg is associated with a sig ni \201 - cantly increased risk of ventilatory failure. Particularly limb-girdle muscular dystrophy, dystrophin- opathies (Becker and Duchenne), fa scioscapulohumeral dystrophy, and dysferlinopathy. Ask about family history. Female carrier s of dystrophin- opathies may develop a milder form with onset of muscle weakness from late teens onwards. Pattern of weakness varies, but may mimic PM, although onset tends to be sl ower. A very high CK, more > \227100 the upper limit of the refer- ence interval may be a p ointer towards dysferlinopathy. EMG features may be indistinguishable from PM. Muscle biops y may show in \202 ammatory in \201 ltrates. Investigations for interstitial lung disease \200 \200 CXR: low sensitivity for ILD. Pulmonary function tests: restrictive pattern with reduced lu ng volumes, normal or raised FEV1/FVC ratio, and a reduced carbon monoxide transfer factor (DLCO). High-resolution computerized tomography (HRCT) demonstrates the extent and severity of disease and helps to distinguish active disease, manifest as ground- glass shadowing, f rom the honeycomb appearance of established \201 brosis. Bronchoalveolar lavage may be he lpful in assessing disease activity and excluding other causes of ILD. Lung biopsy is seldo m required, but may be prognosti- cally useful. \200 Metabolic myopathies (see also p. 293) \200 May present with onset of progressive muscle weakness in adult life. Ask about exertion-ind uced myalgia and pigmented urine (myoglobinuria). Endocrine disorders \200 Hypothyroidism induces proximal myopathy and commonly causes an elevated CK. Hyperthyroidis m, osteomalacia, and parathyroid dysfunction may cause proximal myopathy, but CK is normal. Male hypogonadism may cause loss of muscle mass and fatigue. Acromegaly and Cushing \200 \231s syndrome are usually clini- cally apparent by the time they cause signi \201 cant mu scle weakness. Investigations for cardiovascular disease \200 ECG is mandatory for all patients to detect conduction defects, arrhythmias and evidence of ischaemia. Echocardiography may be abnormal in up to 62% of patients with myositis. Left v entricular diastolic dysfunc- tion and mitral valve prolapse are the most common abnormalit ies. POLYMYOSITIS 286 CK can be very modestly (but signi \201 cantly and persistently) elevated in sarcoid myopa thy. Drugs \200 \200 \200 A full medication history is mandatory. Glucocorticoids are an important cause of myopathy. Additionally, the following drugs have been reported, amongst others, to cause a myopathy (those marked * are more likely to be painful): lithium, chloroquine- containing drugs*, cl o \201 brate, statins, salbutamol, penicillin, colchicine, D-penicillamine*, sulphonamides , hydralazine, ciclosporin, phenytoin, cimetidine* (muscle cramps), zidovudine, carbimazole , and tamoxifen. Compared with PM, in steroid myopathy, the CK is normal and biopsy is cons istent with non-in \202 ammatory \201 bre atrophy. GC-induced myopathy should be conside red during GC treatment, especially if there is no response to treatment. The myositis occu rring with D-penicillamine is not daily dose- or cumulative dose-dependent. It can be life threatening. Mild myoarthralgia may be caused by a number of commonly used drugs, e.g. prot on pump inhibitors and quinolone antibiotics. Alcohol in excess and some illegal drugs (e.g . ecstasy) are associated with severe toxic myopathy occasionally resulting in rhabdomyolys is. Treatment Objectives of management \200 \200 \200 \200 \200 To improve muscle strength. Control extra-muscular complications. Avoid treatment related s ide effects. Early identi \201 cation of malignancy. Maintain function and quality of life . Physical therapies Exercise and management of muscular function \200 Exercise programs used in conjunction with pharma- cotherapy are effective in PM/DM. Bene \201 ts include improved muscle strength, increased exercise tolerance and prevention of mu scle atrophy. There is no evidence that exercise worsens muscle in \202 ammation as had pr eviously been suggested. Programs should be tailored to patients \200\231 capabilities. Pas sive stretching exercises are utilized for bed-bound patients. Oral creatine supplements ha ve been shown to provide additional improvements in muscle function. Patients with dysphagi a or dysphonia require input from speech and language therapists. Arti \201 cial feeding m ethods are occasionally necessary. \200 Other \200 Neurological diseases: motor neuron disease, spinal muscular atrophy and myasthenia gravis. Guillain \200\223Barre syndrome and subacute myelopathy. Viral infection, e.g. HIV, HTLV-1 can induce myositis indistinguishable from PM. Other types of in \202 ammatory myositis, e.g. eosinophilic myositis, granulomatous myositis, macrophagic myofas- ciitis. \200 Immunsuppression There have been very few good quality controlled trials in PM and treatmen t therefore remains mostly empirical, varying according to individual clinician experience and preference. This was highlighted in a recent Cochrane review (Choy, 2005). \200 Glucocorticoids (GCs) are used \201 rst-line, often in con- junction with another immunos uppressive agent (usually azathioprine or methotrexate). Other immunosuppressants, IVIG, or biological agents are indicated in refractory disease. The approach to therapy is broadly similar for PM and DM; however, PM is more likely to be resistant to treatment. Pitfalls with interpreting CK results \200 The reference range of CK can differ depending on ethnic background. It is generally regard ed that people of Afro-Caribbean background have a higher \200\230normal \200\231 referenc e range CK compared with Caucasians. There is allelic variation in the CK gene and post- tr anslational changes that can affect routine CK assays. Glucocorticoids (GCs) GCs have never been adequately evaluated in a randomized controlled t rial (RCT), but are generally accepted as being effective. In retrospective series, muscle weakness improved in up to 88% of those treated. However, up to 50% of patients with PM fai l to respond to GCs alone. \200 Key points regarding differential diagnosis Features that should prompt consideration of al ternative diagnoses \200 Asymmetric pattern of weakness or predominantly distal weakness is more typical of IBM. Mus cle pain and tenderness with normal strength is more suggestive of \201 bromyalgia or pol ymyalgia rheumatica. Family history of neuromuscular disease. Familial cases of PM have bee n observed, but are very rare. Slow onset myopathy that evolves over months to years then c onsider IBM or muscular dystrophy. A typical dosing regime: prednisolone 1 mg/kg per day (up to 80 mg daily). Lower doses may be used in milder disease. Pulse iv methylprednisolone (1 g/day for 3 days) in acute, sever e disease but evidence only in case series. After 4 \200\2236 weeks, once improvement is se en, the dose is gradually tapered to maintenance of 5 \200\22310 mg daily. Rapid GC withdra wal may precipitate disease exacerba- tions. Once dose is reduced to 10 mg, weaning should occur at a maximum of 1mg every 2 \200\2234 weeks. Patients should be warned about side eff ects. Prophylaxis against GC-induced osteoporosis (with calcium and vitamin D supplements t o avoid secondary hyper- parathyroidism and Hypovitaminosis-D) and a bi sphosphonate if >65 years, or if the spine, femoral neck, or total hip T-score on DXA scan in \200\2231.5 or less (see p. 408). It is important to be aware that production of macro-CK can present with elevated routine C K results. Macro-CK may be a normal variant but can be associ- ated with malignancy. A scre en for tumors may be necessary. CK can be elevated secondary to muscle trauma. If modest el evations in CK are thought to arise from trauma, a delay before re-testing is prudent. CHAPTER 8 Autoimmune connective tissue diseases 287 The response to GCs is variable, but tends to be slower than in other autoimmune diseases. Three months may elapse before a demonstrable improvement in muscle weakness is seen. In pa tients who fail to respond to GCs consider: \200 \200 \200 Ciclosporin acts more rapidly than azathioprine and may be an appropriate second line agent . Tacrolimus Some evidence for ef \201 cacy from small case series in refractory PM/DM. Tacr olimus may be particularly effective in ILD associated with myositis. alternative diagnoses; the presence of an unrecognized malignancy; GC-induced myopathy (esp ecially if the CK has fallen but weakness fails to improve or worsens); muscle atrophy with irreversible loss of muscle strength; ongoing active PM (CK may be persistently elevated). \200 In GC failure, MR scanning or repeat EMG may be helpful to assess disease activity. In the presence of diagnostic uncertainty the muscle biopsy should be re-examined and furt her biopsy considered looking for in \202 ammation, alternative diagnoses, or GC-induced m yopathy. If the latter is suspected then it is reasonable to try lowering the prednisolone dose and monitoring the muscle strength response. Mycophenolate mofetil Appears promising from anecdotal reports in treating refractory disea se, although serious opportunistic infec- tions have been reported. Cyclophosphamide Several case series have demonstrated limited ef \201 cacy in improving m uscle strength. Cyclophosphamide is generally reserved for recalcitrant disease unresponsiv e to other treatments. In a recent series of 17 patients with PM/DM and ILD, 12 showed some improvements in lung disease with cyclophosphamide. Intravenous immunoglobulin G (IVIG) Open studies of IVIG in treatment-refractory PM and DM have shown response rates ranging from 75 to 93%. \200 Other immunosuppressants Methotrexate (MTX) and azathioprine (AZA) and are the standard sec ond line immunosuppressive agents. They may be commenced from the outset in conjunction wit h pred- nisolone, particularly in patients with severe disease or major organ involvement. Alternatively, they may be added later in those who respond poorly to prednisolone, relapse during withdrawal, or experience GC-related side-effects. \200 There has been a double-blind placebo controlled randomized controlled trial (DBPRCT) demon strating ef \201 cacy of IVIG in refractory DM but none in PM. The risk of side effects wi th IVIG is low but treatment ef \201 cacy is of limited duration, usually four to six week s, and repeated monthly courses are generally required for sustained effect. The usual dose regime is 2g/kg per month (given over 2 \200\2235 days) for 4 \200\2236 months. MTX is often preferred as the response is seen more rapidly (AZA may take up to 4 \200\2236 months to work). When MTX and AZA were compared in a double-blind randomized controlled tr ial (DBRCT), they had equivalent ef \201 cacy but MTX was better tolerated. AZA may be pre ferable in certain patients, e.g. in women of child-bearing age as it is considered safe in pregnancy, or in patients with liver disease or high alcohol intake who are at increased r isk of hepatotoxicity with MTX. Rituximab Appears promising based on case reports and small case series in both PM and DM. Rituximab has potential advan- tages over IVIG in that it is cheaper and may be more likely to give prolonged disease control. Plasmapheresis A DBPCRCT in 39 patients with PM/DM showed no signi \201 cant bene \201 t. Anti-TNFA Results from several small case series of patients with PM/ DM treated with In \202 iximab or Etanercept suggested that some patients may bene \201 t. However, in a rece nt series of 13 patients with refractory PM/DM treated with In \202 iximab, muscle strengt h failed to improve in any of the patients and several showed clinical and radiological wor sening. Methotrexate In retrospective series, approximately 75% of patients with PM/DM derived bene \201 t from MTX. \200 \200 There has been no RCT comparing MTX with placebo. MTX is administered once a week either or ally or parenterally. The dose is usually 15 mg/week, increasing up to a maximum of 25 mg/w eek. The risk of side effects is reduced by the concurrent use of folic acid 5 mg per week. Other Whole body or total lymphoid radiation have been reported to be effective in small se ries of treatment refractory patients, but adverse effects are common and the risk of malig nancy is a major concern. Azathioprine \200 There are case series supporting the ef \201 cacy of AZA in PM, but the only RCT failed to show a signi \201 cant bene \201 t over placebo. However, the follow-up period of 3 mont hs may have been too short. In a subsequent open study of the same patients, those receivin g GCs plus AZA had a better outcome at 3 years than those receiving GCs alone. The starting dose of AZA is 50 \200\223100 mg per day, increas- ing by 50 mg at weekly intervals as tol erated up to 3.0 mg/kg/day (maximum dose usually 200 mg/day). Treatment duration The optimum duration of therapy has not been established. Long-term GCs should be avoided and, in the absence of disease \202 ares, a total of 9 \200\22312 month s treatment is stan- dard. Immunosuppressants should be continued until patients have been off GCs for >6 months and then withdrawn slowly with close monitoring for relapse. Prognosis Data on long-term outcome in PM/DM are limited. Disease course is extremely varia ble, ranging from mild weakness that improves with GCs to severe, relentlessly progressive muscle failure that is resistant to all therapies. Ciclosporin Evidence from case reports and small retrospective case series is supportive. A RCT comparing MTX with ciclosporin A (both in conjunction with GCs) in 36 patients with PM / DM demonstrated similar ef \201 cacy for the two treatments. POLYMYOSITIS 288 Although the majority of patients improve with initial treatment, only a proportion of thes e achieve long-term clinical remission. Approximately a third of patients are refractory to treatment. Even those who respond often have signi \201 cant residual disability or adver se effects from treatment e.g. fractures or osteonecrosis from GC use. Mortality is increas ed in patients with in \202 ammatory myositis, although survival has signi \201 cantly im proved following the introduction of GCs. The 5-year survival is currently around 95%, and 10-year survival 85 \200\22389%. Common causes of death are cardiac (arrhythmia, heart fail ure, myocardial infarction), pulmonary (ILD, aspiration pneumonia), malignancy, and infecti on. Poor prognostic factors include: \200 \200 \200 \200 \200 \200 decisions. Patient perception of disease, and evaluation of function and quality of life ar e paramount. Follow-up A co-ordinated multi-disciplinary approach should be adopted involving physicians , physiotherapists, occupa- tional therapists, and nurse practitioners with further special ist input as required. Close monitoring with a minimum of 3-monthly assessments is recommen ded for the \201 rst year, reducing in frequency once disease control is established. Current controversies \200 \200 Diagnostic criteria remain a highly contentious area. Interaction of immune and non-immune mechanisms in disease pathogenesis. Clarifying distinctions between PM, DM and IBM. What is the risk of malignancy in PM? Role of biologic therapies in myositis. Assessment of diseas e activity and development of robust outcome measures. \200 \200 \200 older age; interstitial lung disease; presence of anti-Jo1 antibodies; bulbar muscle weakne ss; cardiovascular involvement; delayed treatment. Resources Assessment tools MITAX: Myositis intention to treat index. MYOACT: Myositis disea se activity assessment. MDI: Myositis damage index. SF-36: Short form 36. Monitoring disease activity Improvements in muscle strength should be the principal target of treatment. However, distinguishing active in \202 am- matory disease from established m uscle damage is problem- atic. Combinations of muscle enzymes, EMG and imaging are employed to discriminate but none are de \201 nitive. Patient organizations Muscle strength Manual muscle testing (MMT) remains the most frequently used method for ass essing muscle power. \200 The Myositis Support Group (UK). Available at: www. myositis.org.uk The Myositis Associatio n (US). Available at: www. myositis.org IMACS advocated the use of the MMT-8 in assessing outcome in clinical trials. This involves testing eight spec- i \201 ed muscle groups against resistance and grading power from 0 t o 5 or 0 to 10 using a modi \201 ed Medical Research Council scale [see IMACS website]. Th e total MMT score (sum of the individual muscle scores) is used to serially monitor changes in muscle strength. MMT has the advantages of being partially validated with reasonable in ter-observer reliability, and is relatively quick and easy to perform. Isometric testing, w ith hand-held dynamometers, may provide more accurate, objective assessment of muscle stren gth, and is easy to perform in a clinic setting. Computerized dynamometers are also availab le, but are more time-consuming and are not widely used. Internet Sites International Myositis Assessment and Clinical Studies Group (IMACS), for ma nual muscle testing guidelines, grading scheme and score chart, and details of tools for as sessing disease activity, damage and patient reported outcomes in myositis. Available at: w ww.niehs.nih.gov/ research/resources/collab/imacs/main.cfm Dysferlinopathy. See article by Masashi Aoki. Available at: www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book= gene&partid=1303 ICD-10 codes M33.2 M36.0 M33.9 J99.1 Polymyositis Dermato(poly)myositis in neoplastic disease Dermatopolymyositis Respiratory di sorders in diffuse CT disease Biochemical monitoring Muscle enzymes (CK plus one other) should be checked at least monthl y during the initial phase of treatment. This is a guide to disease activity and may help p redict relapse. However, muscle enzymes may not always correlate with degree of ongoing in \202 ammation, e.g. some treatments may suppress CK with no improvement in weakness. See also: Dermatomyositis Metabolic myopathies Inclusion body myositis p. 290 p. 522 p. 302 References Alexanderson H, Dastmalchi M, Esbjornsson-Liljedahl M, Opava CH, Lundberg IE. Be ne \201 ts of intensive resistance training in patients with chronic polymyositis or derma tomyositis. Arthritis Rheum 2007; 57: 768 \200\22377. Imaging MR, MRS, and US may be helpful, but their role in disease monitoring has yet to be established. Other measures Patients should be assessed for the presence of extra- muscular manifestatio ns, which will impact on management Alexanderson H, Lundberg IE. Disease-speci \201 c quality indicators, outcome measures and guidelines in polymyositis and dermato- myositis. Clin Exp Rheumatol 2007; 25(6 Suppl 47): 153 \200\2238. CHAPTER 8 Autoimmune connective tissue diseases 289 Bohan A, Peter JB. Polymyositis and dermatomyositis ( \201 rst of two Hengstman GJ. Advances in the immunopathophysiology of the idiopathic in \202 ammatory myo pathies: not as simple as suspected. Curr Rheumatol Rep 2007; 9(4): 280 \200\2235. parts). N Engl J Med 1975; 292(7): 344 \200\2237. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975; 292(8): 403 \200\2237. Hengstman GJ, Brouwer R, Egberts WT, Seelig HP, Jongen PJ, van Venrooij WJ, et al. Clinical and serological characteristics of 125 Dutch myositis patients. Myositis speci \201 c aut oantibodies aid in the differential diagnosis of the idiopathic in \202 ammatory myopathie s. J Neurol 2002; 249: 69 \200\22375. Bohan A, Peter JB, Bowman RL, Pearson CM. Computer-assisted analysis of 153 patients with p olymyositis and dermatomyositis. Medicine (Baltimore) 1977; 56(4): 255 \200\22386. Bunch TW. Prednisone and azathioprine for polymyositis: long-term Hengstman GJ, De Bleecker JL, et al. Open-label trial of anti- TNF-alpha in dermato- and po lymyositis treated concomitantly with methotrexate. Eur Neurol 2008; 59(3-4):159 \200\22363 . followup. Arthritis Rheum 1981; 24: 45 \200\2238. Cherin P, Pelletier S, et al. Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty- \201 ve adult pa tients. Arthritis Rheum 2002; 46:467 \200\22374. Isenberg DA, Allen E, et al. International consensus outcome meas- ures for patients with i diopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology (Oxford) 2004; 43: 49 \200\22354. Chinoy H, Salway F, et al. Tumor necrosis factor-alpha single nucle- otide polymorphisms ar e not independent of HLA class I in UK Caucasians with adult onset idiopathic in \202 amma tory myopathies. Rheumatology (Oxford) 2007; 46: 1411 \200\22316. Lundberg IE. The heart in dermatomyositis and polymyositis. Rheumatology (Oxford) 2006; 45 Suppl 4:iv18 \200\22321. Choy EH, Hoogendijk JE, Lecky B, Winer JB. Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev 2005; (3): CD003643. Choy EH, Isenberg DA. Treatment of dermatomyositis and polymy- Miller FW, Leitman SF, et al. Controlled trial of plasma exchange and leukapheresis in poly myositis and dermatomyositis. N Engl J Med 1992; 326(21): 1380 \200\2234. Miller F, Walsh Y, Saminaden S, Lecky B, Winer J. Randomized double blind trial of methotre xate and steroids compared with azathioprine and steroids in the treatment of idiopathic in \202 ammatory myopathy. J Neurol Sci 2002; 199(Suppl 1): S53. ositis. Rheumatology (Oxford) 2002; 41: 7 \200\22313. Chung YL, Alexanderson H, et al. Creatine supplements in patients with idiopathic in \202 ammatory myopathies who are clinically weak after conventional pharmacologic treatment: Six -month, double- blind, randomized, placebo-controlled trial. Arthritis Rheum 2007; 57: 694 \200\223702. Mok CC, Ho LY, To CH. Rituximab for refractory polymyositis: an open-label prospective study. J Rheumatol 2007; 34: 1864 \200\2238. Oddis CV, Rider LG, Reed AM, Ruperto N, Brunner HI, Koneru B, et al. International consensu s guidelines for trials of therapies in the idiopathic in \202 ammatory myopathies. Arthri tis Rheum 2005; 52: 2607 \200\22315. Cordeiro AC, Isenberg DA. Treatment of in \202 ammatory myopathies. Postgrad Med J 2006; 82(969): 417 \200\22324. Dalakas MC. Mechanisms of disease: signaling pathways and immu- nobiology of in \202 ammat ory myopathies. Nat Clin Pract Rheumatol 2006; 2(4):219 \200\22327. Rider LG, Giannini EH, et al. De \201 ning Clinical Improvement in Adult and Juvenile Myositis. J Rheumatol 2003; 30:603 \200\22317. Dalakas MC. The role of high-dose immune globulin intravenous in the treatment of dermatomy ositis. Int Immunopharmacol 2006; 6: 550 \200\2236. Sultan SM, Ioannou Y, Moss K, Isenberg DA. Outcome in patients with idiopathic in \202 amm atory myositis: morbidity and mortality. Rheumatology (Oxford) 2002; 41: 22 \200\2236. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet Vencovsky J, Jarosova K, Machacek S, Studynkova J, Kafkova J, Bartunkova J, et al. Cyclospo rine A versus methotrexate in the treatment of polymyositis and dermatomyositis. Scand J Rh eumatol 2000; 29(2): 95 \200\223102. 2003; 362(9388): 971 \200\22382. Danko K, Ponyi A, Constantin T, Borgulya G, Szegedi G. Long-term survival of patients with idiopathic in \202 ammatory myopathies according to clinical features: a longitudinal stud y of 162 cases. Medicine (Baltimore) 2004; 83:35 \200\22342. Villalba L, Hicks JE, Adams EM, Sherman JB, Gourley MF, Leff RL, et al. Treatment of refrac tory myositis: a randomized crossover study of two new cytotoxic regimens. Arthritis Rheum 1998; 41: 392 \200\2239. Yamasaki Y, Yamada H, et al. Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/ dermatomyositis. Rheu matology (Oxford) 2007; 46: 124 \200\22330. Dastmalchi M, Grundtman C, et al. A high incidence of disease \202 ares in an open pilot study of in \202 iximab in patients with refractory in \202 ammatory myopathies. Ann Rheu m Dis 2008. Fathi M, Lundberg IE. Interstitial lung disease in polymyositis and dermatomyositis. Curr Opin Rheumatol 2005; 17: 701 \200\2236. DERMATOMYOSITIS 290 Dermatomyositis De \201 nition Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized b y muscle in \202 ammation and cuta- neous manifestations. It is part of a heterogeneous gr oup of in \202 ammatory myopathies including polymyositis (PM) and inclusion-body myositis (IBM). DM may present in an isolated form or in association with malignancy or other autoi mmune connective tissue diseases. For a de \201 nite diagnosis of DM three of four criteria plus the rash must be present. T hese criteria have never been validated or revised, and criticisms of this system exist, es pecially as it fails to dis- tinguish PM from IBM (as the latter was not recognized until t he 1980s) and the criteria were formulated prior to testing for myositis speci \201 c auto antibodies (MSAs). More recent diagnostic criteria based on histopathologic change have bee n proposed by Dalakas. These have not been formally validated. Epidemiology DM is a rare disease and only a few epidemiological studies have been publishe d. It has a prevalence of approximately 1 per 100 000 in the North American population and affects all ages. The peak incidence is 40 \200\22350 years. There is a female predominance with a ratio of 2:1. Clinical features Key features in history Musculoskeletal \200 Symptoms can start insidiously \200\223 typically dif \201 culty with everyday tasks, suc h as rising from a chair, climbing stairs, lifting objects, brushing their hair, or shaving . Myalgia is not a common complaint. Dysphonia can be noticed by relatives. Patients usuall y have fatigue and can complain of joint pains \200\223 usually small joints. Etiology and pathophysiology Genetics There is still much to learn about the genetics of DM . Recently work had been published demonstrating that HLA susceptibility markers differ in diverse myositis phe- notypes and certain genotypes are more closely associated to serology than myositis subtype \200 \200 Key features on examination Musculoskeletal \200 Environmental triggers No clear precipitating triggers identi \201 ed. DM presents with varying degrees of muscle weakness, which develops insidiously over weeks to months, but acutely in rare cases. DM, like PM, primarily affects the proximal muscles a nd is generally symmetrical. Testing power in trapezius, del- toids, biceps brachii, quadri ceps, and hip stabilizers is essential. Strength is scored out of \201 ve using the Medic al Research Council (MRC) scale (in which zero is the low- est score and \201 ve the high est). There are no sensory de \201 cits and re \202 exes may be absent in severe weakness . Distal muscle involvement occurs late in the disease and \201 ne motor movements may th en be affected. Facial muscles remain normal and the extra-ocular mus- cles are never affec ted as compared to myasthenia gravis where frequent involvement of facial and oculobulbar m uscles occurs. The neck extensor muscles may be involved causing head drop and pelvic stabi lity can be lost. With advanced disease dysphagia, aspiration, and respi- ratory muscle wea kness can occur. Immunopathology DM is thought to be a humorally-mediated microangiopathy affecting skin and muscle, where the cellular in \201 ltrate is located in perifascicular regions around blo od vessels. \200 The trigger of the initial capillary injury is still unknown. It has been proposed that inj ury results from autoantibody production against an endothelial antigen. Complement activat ion occurs early and has a clear role in the pathology. The terminal complement C5 \200\223 9 mem- brane attack complex is detectable in vessel walls before the appearance of an in \202 ammatory cell in \201 ltrate. It is still unclear whether the vasculopathy is primari ly complement mediated or secondary to other events. Muscle damage probably occurs from isc haemia second- ary to capillary damage. The in \202 ammatory in \201 ltrate is composed p redominantly of B cells and CD4+ T cells. Plasmacytoid dendritic cells are abundant in DM m uscle; however, their exact role in the pathogenesis is yet to be con \201 rmed. The pro-i n \202 ammatory cytokines IL-1 and TNFA are increased in the muscle tissue of patients wit h DM and may contribute to muscle weakness. Dermatological clinical features The characteristic rash in dermatomyositis accompanies or precedes muscle weakness. Common cutaneous manifes- tation of DM include: \200 Risk factors No known risk factors. Diagnostic criteria There are no accepted diagnostic cr iteria for DM. \200 A heliotrope rash (violaceous to dusky erythematous rash on eyelids occasionally with oedem a). It is rarely seen in other autoimmune connective tissue disorders. Gottron \200\231s pa pules are found over the metacarpophalan- geal joints and proximal interphalangeal joints. These are slightly raised violaceous papules and plaques. Papules may also be found overlyi ng the elbows, knees, or feet. These may appear scaly and psoriaform. An erythematous rash on the face, neck and anterior chest (V sign) or back and shoulders (shawl sign). Nail-fold changes of periungal telangiectasia, cuticular hypertrophy, and small haemorrhagic infarct s. Bohan and Peter formulated classi \201 cation criteria in 1975 de \201 ning 5 major crite ria for diagnosing both PM and DM: \200 \200 \200 \200 \200 symmetrical muscle weakness; muscle biopsy evidence of in \202 ammation; elevation of seru m muscle enzymes; EMG evidence of myositis; cutaneous features of Gottron \200\231s papules , heliotrope rash and an erythematous rash in a shawl like distribution (see Plate 7 and 8) . CHAPTER 8 Autoimmune connective tissue diseases 291 Table 8.11 Pathological features of polymyositis (PM) and dermatomyositis (DM). Criterion PM Myopathic DM Amyopathic DM de \201 nite De \201 nite Probable De \201 nite Probable Myopathic muscle weakness Yes Yes Yes Yes No EMG \201 ndings Myopathic Myopathic Myopathic Myopathic Myopathic or non-speci \201 c Muscle enzymes High (up to 50 times normal) High (up to 50 times normal) or normal High (up to 50 times normal) High High (up to 10 times normal) or normal Non speci \201 c or diagnostic for DM (subclinical myopathy) Perifascicular perimysial or perivascular in \201 ltrates with perifascicular atrophy Perifascicular perimysial or perivascular in \201 ltrates with perifascicular atrophy Ubiquitous HLA class-1 expression, but no CD8+ T-cell in \201 ltrates or vacuoles Muscle-biopsy \201 ndings Primary in \202 ammation, with the CD8+ T-cell/ HLA class-1 complex and no vacuoles Rash or calcinosis Absent Absent Present Not detected Present PM, polymyostitis; DM, dermatomyositis; EMG, Electromyography; HLA, Human Leucocyte Antigen . Adapted from Dalakas and Hohlfeld 2003, with permission. A photosensitive rash characterized by an erythematous to violaceous psoriaform dermatitis. Calcinosis of the skin or muscle. It is commoner in juve- nile DM. Calcinosis cutis occurs over bony prominences and can lead to ulceration and infection. Amyopathic dermatitis (DM- sine-myositis), where muscle strength is normal, but there is skin disease. However, muscle MR and biopsy is often abnormal. The association with other in \202 ammatory myopathies is less clear and the associated re ported rates are lower. There is no correlation between the severity of the myopathy and oc currence of malignancy. Malignancy may not be obvious. Clinical examination of abdomen, pel vis, breast, and rectum and for lymph nodes is important (see below). The most common malig nancies in decreasing order of frequency are: ovarian \200 lung; \200 pancreatic; \200 non-Hodgkin lymphoma; \200 stomach; \200 colorectal. \200 In Asian populations ther e is a higher incidence of nasopharyngeal carcinoma. Malignant disease may occur before the onset, concurrently or after the onset of myositis. Co-morbidities Systemic and other clinical features DM is a multisystem disorder. Extra-mus cular involvement may be present in up to 50% of patients. \200 Systemic features include fever, weight loss, anorexia, and fatigue. Pulmonary disease occu rs in up to 30% of patients and includes ILD. The strongest predictor of ILD is anti-Jo-1 a ntibody; however, ILD may occur in its absence. Respiratory muscle weakness can lead to hyp oventila- tion and respiratory compromise. Arthritis is found in up to 25%. It is symmetric al and non-deforming. Usually, the small joints are involved, and patients complain of pain and morning stiffness. Oesophageal disease is present in up to 50% of patients and manifes ts as dysphagia. Striated muscle involvement of the pharynx or proximal esophagus leads to proxi- mal dysphagia. This correlates with severity of muscle disease and is steroid respon sive. Distal dysphagia sug- gests involvement of non-striated muscle. It tends to be more c ommon in those with an overlap disorder. Dysphagia often indicates a poor prognosis. Cardia c involvement may occur in up to 50% of patients causing conduction defects, arrhythmias, p ericarditis, and valvular heart disease. Only a small percentage of those with cardiac invo lvement are symptomatic. Overlap syndromes Reports estimate that between 11 \200\22340% of patients with PM or DM ha ve an associated autoimmune connective tissue disease. DM has most commonly been described in association with systemic sclerosis (SSc) and MCTD. Investigations Laboratory Blood test s are important to assess the severity of disease, to help guide treatment, and to monitor for the complica- tions of the disease and/or treatment. \200 Initial investigations should include urinalysis, fecal occult blood assessment. FBC/CBC ma y show evidence of anemia of chronic disease or thrombocytosis with active in \202 ammatio n. Abnormalities in renal function may be seen in overlap syndromes (e.g. SLE). LDH, AST, a nd ALT may be elevated. Malignancy There is an association between DM and cancer. The reported rate is 20 \200\2232 5% in adults >45 years old. DERMATOMYOSITIS 292 MR imaging identi \201 es an appropriate area for muscle biopsy, as muscle involvement may be patchy. Baseline tests are important to guide the feasibility of therapeutic options (e.g. methotre xate). ESR and CRP are usually elevated, but if normal do not rule out a diagnosis of myosi tis. Creatine kinase (CK) can be increased up to 50 times the upper limit of the reference interval, although it can be normal CK can also be low in those with advanced disease and s igni \201 cant loss of muscle mass. Myoglobin in serum and urine rises with active disease and can be detected in 70 \200\22380% of patients. Serum myoglobin levels increase earlier than CK and normalize faster. Myoglobinuria is less common. Vitamin D levels to exclude lo w vitamin D as a contribu- tory cause for muscle weakness. Testosterone and LH in males to rule out hypogonadism \200\223 can cause fatigue and reduced muscle mass. Histology When the diagnosis is suspected on clinical grounds a de \201 nitive diagnosis c an be con \201 rmed on histology. Muscle is the preferred tissue though in some cases skin biopsy can be helpful. \200 On haematoxylin and eosin the cellular in \201 ltrate is seen in perifascicular regions ar ound blood vessels. Myo \201 bre necrosis and regeneration and perifascicular atrophy are characteristic in DM. Using appropriate immunohistochemistry stains, com- plement C5 \200 \2239 and immune complexes are detectable in vessel walls. The in \202 ammatory in \201 l trate consists of primarily B cells, macrophages, and CD4+ T cells. In PM the in \202 amma tory in \201 ltrate is endomysial, consists primarily of CD8+ T cells and there is no evid ence of immune deposits. In muscular dystrophy the in \202 ammatory cell in \201 ltrate i s endomysial, but is limited to areas adjacent to necrotic muscle \201 bres Autoantibodies ANA is positive in 80% of patients with in \202 ammatory myositis (either P M or DM). \200 Autoantibodies associated with DM can be divided into two groups: Myositis-speci \201 c au toantibodies (MSA) and Myositis-associated autoantibodies (MAA). The three main groups of M SAs are: \200 Other investigations Electromyography (EMG) EMG can distinguish myopathic from neuropathic weak- ness and it has a role in targeting a site for muscle biopsy. \200 anti-aminoacyl transfer-RNA (tRNA) synthetase autoantibodies. Anti-Jo-1 antibody (against h istidyl- tRNA synthetase) is the commonest occurring of the six autoantibodies in this grou p. These MSAs charac- terize \200\230Antisynthetase Syndrome \200\231 (myositis, interstit ial lung disease, arthritis, mechanic \200\231s hands and Raynaud \200\231s phenomenon); an ti-signal recognition peptide (SRP). These occur almost exclusively in PM; anti-Mi-2. Direc ted against the helicase family of proteins. This antibody has a frequency of 20% in DM and is more common in DM than in PM. Characteristic EMG changes show evidence of increased membrane irritability manifest as: \200 increased insertional activity and spontaneous \201 brillations; abnormal myopathic low a mplitude short duration polyphasic motor potentials; complex repetitive discharges. EMG abnormalities support the diagnosis of DM, but are not diagnostic. More recently, a speci \201 c autoantibody (anti-CADM-140) has been identi \201 ed in pat ients with clinical amyopathic DM. The target antigen remains unknown. It may be associated with a subset of DM with cutaneous manifes- tations and ILD but no muscle symptoms. Anti-p 155 antibody has also recently been reported in DM. The target antigen is a transcriptional intermediary factor and, thus far, has a frequency of 20% in DM espe- cially in cancer-ass ociated disease. MAAs correlate with myositis overlap syndromes. Anti-U1 RNP de \201 nes m ixed connective tissue disease (MCTD). Anti-Ku and anti-PM-Scl characterize PM/SSc overlap syndrome. Respiratory investigations There is an association of DM with lung pathology (ILD or thorac ic muscular weakness). \200 