 \200 HELLP \200\223 haemolysis elevated liver enzymes and low platelets is a pregnancy-related hypertensive disorder with underlying thrombotic microangiopathy; defec- tive control of th e alternative pathway of complement may be responsible. HELLP is sometimes considered to be a form of pre-eclampsia. Pre-eclampsia \200\223 new hypertension and proteinuria during t he second half of pregnancy are associated with placental ischaemia; may progress to the co nvul- sive state of eclampsia. Histology \200 Renal biopsy should be considered in patients with an \200\230active \200\231 renal sedime nt on urinalysis or isolated proteinuria (+++ or >1g/L). Liaise with renal team. See p. 75. Skin biopsy may reveal thrombotic microangiopathy. In \201 ltration of in \202 ammatory cells may also be evident. Other investigations \200 Treatment Objectives of management \200 \200 \200 \200 Pulmonary function tests. Spirometry and transfer factor to screen for pulmonary arterial h ypertension. See also p. 59. Echocardiogram to detect any pericardial effusion, LVH, reduce d LV ejection fraction, valvular lesions, and as a screening test for PAH. ECG \200\223 us eful screen for arrhythmia, ischaemia, left ventricular hypertrophy (LVH). Ankle/Brachial P ressure index, Doppler ultrasound, MR angiography or conventional angiography to investigat e suspected peripheral vascular disease. Carotid ultrasound for investigation of carotid br uit or of TIA/stroke. Lumbar puncture, EEG and other neurophysiology tests might be necessa ry (see also p. 90). Ocular investigations, \200\223 see The Eye, p. 48. Prevention of thromboembolic events. Management of any associated in \202 ammatory disease . Management of associated co-morbidity. Maximizing chance of successful pregnancy, whilst minimizing risks to mother. Prevention of thromboembolic events Anticoagulation The evidence base regarding ef \201 ca cy of antiplatelet and anticoagulant agents is still inadequate. Published RCTs include mai nly cases at the low-risk end of the APLS spec- trum and it is likely that high-risk APLS p atients should be anticoagulated more aggressively than these trial data would suggest (Tab le 8.9). Hydroxychloroquine (HCQ) Several studies have indicated that HCQ reduces throm- botic event s in SLE. Further study is required to assess its ef \201 cacy in primary APLS, but in vie w of its relative safety, it is widely used in all categories of APLS. Differential diagnosis \200 \200 Beh et \200\231s disease - see p. 340. Diffuse intravascular coagulation (DIC) with thromb ocy- topaenia should be considered as a differential diagnosis CHAPTER 8 Autoimmune connective tissue diseases 279 Risk factors Additional risks for thromboembolic disease should also be minimized. This inc ludes stopping smoking, treating hypertension, and managing hyperlipidaemia. Table 8.10 Recommended therapy for pregnant patient with aCL antibodies Pregnancy scenario Recommended treatment HMG-CoA reductase inhibitors (statins) The pleiotropic effect of statins has been reported to in- clude inhibition of APL-mediated up-regulation of tissue factor expression by monocy tes and endothelial cells. Low-dose aspirin? Persistent APL antibodies (LA is higher risk than aCL antibodies), but no previous thrombo- embolism (TE) or adverse obstetric history LMWH post-partum? Low-dose aspirin prophylactic LMWH. Table 8.9 Recommended therapy for categories of (non- pregnant) patients with aCL antbodies APLS with adverse obstetric history (no TE history) LMWH postpartum Category of patient Recommended therapy APLS with TE history Stop warfarin as soon as possible post-conception. Persistent aCL antibodies. No history of clinical events HCQ?* Use low-dose aspirin and therapeutic dose of LMWH then follow with warfarin postpartum Thrombosis and single positive APL antibody test Treat as for thrombosis in the general population APLS ( \201 rst venous thrombosis) Warfarin (INR 2.0 \200\2233.0) and HCQ Warfarin after organogenesis (weeks 6 \200\22312) APLS with recurrent TE disease despite full antithrombotic dose of heparin APLS (arterial or recurrent venous thrombosis) Warfarin (INR 3.0 \200\2234.0) and HCQ Breastfeeding Warfarin or heparin safe APLS (recurrent episodes on warfarin with INR 3.0 \200\2234.0) Low molecular weight or unfractionated heparin or warfarin plus antiplatelet agent Anti-in \202 ammatory treatment Increased leucocyte adhesion and complement activation hav e been demonstrated in placentae of women with APLS and obstetric complications. Heparins h ave been shown to reduce both these processes. Glucocorticoids (GCs) appear to be ineffecti ve and can cause signi \201 cant adverse effects, so should be avoided. HCQ may be bene \201 cial, but there are no outcome data to inform this at present. INR: international normalized ratio. *The APLASA study indicated that patients with persist ent aCL antibodies with or without a lupus anticoagulant did NOT bene \201 t from 81 mg as pirin daily. Management of associated morbidity Refer to SLE section (AICTDs chapter, pp. 250 \200\22325 1) for management of co-morbidity including: cardiovascular dis- ease, osteoporosis, chroni c renal failure, and depression. Pregnancy monitoring and management \200 Blood pressure and urinalysis checked at each antenatal visit at least monthly. FBC for pat ients on heparin to monitor for heparin- induced thrombocytopaenia. This is rare and the ri sk is lower with LWMH than with unfractionated heparin. INR to monitor anticoagulation with warfarin. Antifactor Xa activity can be used to monitor anticoagu- lation with LMWH. Frequ ent ultrasound scans to monitor fetal growth. Uterine and umbilical artery Doppler blood \202 ow analysis during second trimester. Manage hypertension with calcium channel antagoni sts. Calcium and vitamin D3 (e.g. adcal-D3 2 daily) may be given in pregnant and breastfeed ing patients receiving heparin. However, there is no evidence base to indicate whether this reduces the incidence or severity of heparin-induced osteoporosis. Activity of co-existing SLE may be treated with systemic GCs, HCQ, azathioprine, or rituximab. For severe thromboc ytopaenia use prednisolone 30 \200\22360 mg daily. This raises platelet count. If effective use this strategy prior to delivery. Other options include intrave- nous immunoglobulin an d early delivery. Maximizing chance of successful pregnancy whilst minimizing risks to mother Pregnancy plann ing \200 Repeat aCL antibody testing and check LA to establish whether APL antibodies are persistent . In patients with co-existing SLE, optimize disease control on non-teratogenic immunosuppr essants (see p. 368 \200\223369). Postpone pregnancy after a thromboembolic event, especial ly a stroke. Discourage pregnancy in patients with pulmonary hypertension. Determine antico agulant strategy (see Table 8.10). \200 \200 \200 Anticoagulant strategy The recommendations below are distilled from a variety of studies an d reviews. However, treatment regimes for each scenario remain controversial. HCQ appears t o be safe in pregnancy. Either unfractionated heparin or low molecular weight heparin (LMWH ) may be given in: \200 Prophylactic doses: unfractionated heparin 5000 \200\223 10 000 IU twice daily or LMWH, e.g . enoxaparin 0.5 mg/kg twice daily. Therapeutic doses: unfractionated heparin 10 000 \200 \223 36 000 IU twice daily or LMWH, e.g. enoxaparin 1 mg/kg twice daily, with monitoring. Multidisciplinary \200 Obstetrician. \200 Neonatologist. \200 Hematologist. \200 Re nal physician. \200 Dermatologist. \200 Chest physician. \200 Gastroenterologist. Heparin should be suspended for delivery. Stop heparin at least 12 h before an epidural inj ection for prophylactic regimens and at least 24 h before an epidural for therapeu- tic reg imens. In these patients, heparin should be restarted post-partum, provided there are no ha emorrhagic compli- cations and continued for 3 months. ANTIPHOSPHOLIPID SYNDROME 280 \200 \200 Radiologist. Ophthalmologist. Vascular surgeon. Bucciarelli S, Cervera R, et al. Mortality in the catastrophic antiphos- pholipid syndrome: causes of death and prognostic factors. Autoimmun Rev 2006; 6: 72 \200\2235. Crowther MA, Wisloff F. Evidence based treatment of the antiphospholipid syndrome II. Optim al anti-coagulant therapy for thrombosis. Thromb Res 2005; 115: 3 \200\2238. Patient advice \200 \200 Avoid smoking. Education regarding cardiovascular risk and importance of regular aerobic ex ercise, healthy diet, and avoidance of prolonged immobility or oral contraceptive. In pregn ant women with APLS, the probability of a live birth is 75 \200\22380%, with appropriate m anagement. Risks of pre-eclampsia, premature delivery, thrombosis are increased. Erkan D, Harrison MJ, et al. Aspirin for primary thrombosis prevention in the antiphospholi pid syndrome. Arthritis Rheum 2007; 57: 2382 \200\22391. Marie I, Jouen F, et al. Anticardiolipin and anti-beta2 glycoprotein I antibodies and lupus -like anticoagulant: prevalence and signi \201 - cance in systemic sclerosis. Br J Dermato l 2008; 158: 141 \200\2234. Miyakis S, Lockshin MD, et al. International consensus statement on an update of the classi \201 cation criteria for de \201 nite antiphospholipid syndrome. J Thromb Haemost 2006; 4: 295 \200\223306. Resources Guidelines For guidelines on the identi \201 cation of LA, see Brandt et al., 19 95, in references. Norris M, Perico N, Remuzzi G. Mechanisms of disease: pre-eclampsia. Nat Clin Pract Nephrol 2005; 1: 98 \200\223114. Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 2000; 15: 145 \200\22351. Ruiz-Irastorza G, Khamashta MA. The treatment of antiphospholipid syndrome: a harmonic cont rast. Best Pract Res Clinical Rheumatol 2007; 6: 1079 \200\22392. Patient organizations Hughes Syndrome Foundation (Antiphospholipid Syndrome). The Rayne Ins titute, St Thomas \200\231 Hospital, London SE1 7EH. Tel: 020 7960 5561. Available at: www. hughes-syndrome.org Salmon JE, Girardi G, Lockshin MD. Antiphospholipid syndrome as a disorder initiated by in \202 ammation: implications for the therapy of pregnant patients. Nat Clin Pract Rheumatol 2007; 3: 140 \200\2237. Sanna G, Bertolaccini ML, et al. Central nervous system involve- ment in the antiphospholip id (Hughes) syndrome. Rheumatol 2003; 42: 200 \200\22313. ICD-10 codes D68.8 Coagulation defects associated with presence of \200\230SLE inhibitor \200\231. O00.0 Spontaneous abortion in abdominal pregnancy Sherer Y, Blank M, Shoenfeld Y. Antiphospholipid syndrome (APS): where does it come from? B est Pract Res Clinical Rheumatol 2007: 21: 1071 \200\2238. References Amirlak I, Amirlak B. Haemolytic uraemic syndrome: an overview. Uthman I, Khamashta M. Antiphospholipid syndrome and the kidneys. Semin Arthritis Rheum 2006; 35: 360 \200\2237. Wisloff F, Jacobsen EM, Listol S. Laboratory diagnosis of the antiphospholipid syndrome. Th rombosis Res 2003; 108: 263 \200\22371. Nephrol 2006; 11: 21 \200\2238. Belizna CC, Richar V, et al. INsights into atherosclerosis therapy in antiphospholipid syndrome. Autoimmun Rev 2007; 7: 46 \200\22351. Brandt JT, Barna LK, Triplett DA. Laboratory identi \201 cation of lupus anticoagulants: r esults of the Second International Workshop for Identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies of the ISTH. Thromb Haemost 1995; 74: 1597 \200\223603. This page intentionally left blank POLYMYOSITIS 282 Polymyositis De \201 nition Polymyositis (PM) is classi \201 ed as an idiopathic in \202 amma- tory m yopathy, the other members of the group being dermatomyositis (DM) and sporadic inclusion b ody myositis (IBM). PM is characterized by subacute onset of proximal muscle weakness and i n \202 ammatory in \201 ltrates in skeletal muscle. It may occur in association with othe r autoimmune connective tissue diseases. There is overlap between the features of PM and DM , and the respective chapters in this text should be read in conjunction. However, there ar e several key features that distinguish PM from DM, which include: \200 \200 reached that a \200\230de \201 nite \200\231 or \200\230probable \200\231 diagnosis of P M by Bohan and Peter criteria was suf \201 cient for enrolling patients in trials with the proviso that the muscle biopsy must be consistent with PM, and that all other forms of myo pathy must be excluded by clinical, laboratory, genetic, or pathological techniques. Howeve r, the limita- tions of the Bohan and Peter criteria were recognized. A large international , multidisciplinary collaborative project has therefore been set up to develop and validate new classi \201 cation criteria for the idiopathic in \202 ammatory myopathies. Epidemiology PM usually affects adults from the 3rd decade onwards with a peak incidence fr om age 40 \200\22360 years. In contrast to DM, PM very rarely affects children. The female to male ratio is 2:1. Data on the frequency of PM in the general population is lacking. US estimates of the annual incidence of PM and DM combined, range from 2 to 10/million. Absence of the pathognomonic rash of DM. A distinct immunopathological process with charact eristic \201 ndings on muscle biopsy. A lower association with malignancy. Diagnostic criteria Diagnostic and classi \201 cation criteria for the idiopathic inflamma tory myopathies remain a subject of much dispute. Bohan and Peter proposed a set of diagnos tic criteria for PM and DM in 1975 that have been widely used for many years. This incorpor ates \201 ve major criteria. Etiology and pathophysiology PM, DM, and IBM are all characterized by acquired muscle weakn ess and skeletal muscle in \202 ammation, but differ clinically, histologically, and patho physiologically. \200 PM and DM are autoimmune diseases targeted at as yet unidentified antigens within skeletal muscle. In IBM, in \202 ammatory and degenerative processes are evident. The mechanism of muscle damage in PM appears to be predominantly via T-cell mediated cytotoxicity. Muscle bi opsy reveals infiltrates of CD8+ cytotoxic T-lym- phocytes within muscle fascicles. DM is c haracterized by perivascular in \201 ltrates of CD4+ T cells and B cells, with complement- mediated damage of intra-muscular microvasculature and consequent muscle ischaemia. Akin to other autoimmune diseases, PM is thought to arise following exposure to an environmental t rigger in genetically predisposed individuals. Symmetrical proximal muscle weakness with or without dysphagia and respiratory muscle weakn ess. Elevation of serum muscle enzymes, especially CK. Electromyography (EMG) evidence of m yositis. Muscle biopsy abnormalities of degeneration, regen- eration, necrosis, phagocytosi s, and an interstitial mononuclear in \201 ltrate. Typical skin rash of dermatomyositis. \200 \200 PM is classi \201 ed as \200\230de \201 nite \200\231 in the presence of 4 criteria, \200\230probable \200\231 with three criteria and \200\230possible \200\231 with 2. PM is differentiated from DM by the absence of the rash. The classi \201 cation divides the idiopathic in \202 ammatory myopathies into primary id iopathic DM or PM, Juvenile DM/PM, DM/PM associated with malignancy, PM/DM associated with vasculitis, and DM/PM associated with autoimmune connective tissue disease. IBM was identi \201 ed as a distinct clinical entity several years later and is included in the classi \201 cation of in \202 am- matory myopathies. The above criteria have been criticized for lacking speci \201 city and resulting in over-diagnosis of PM as a result of misclassi \201 cation of IBM, and other myopathies. The principal concern is that in \202 ammatory i n \201 ltrates in skeletal muscle may be present in several other condi- tions, for exampl e, muscular dystrophies, toxic myopa- thies and IBM, and these may not be adequately exclud ed under these criteria. Dalakas proposed alternative criteria incorporating more speci \201 c muscle biopsy characteristics. However, these criteria have not been validated and h ave in turn been criticized for being too stringent, with the concern that they would leave many patients with no diagnosis thereby limiting their treatment options (see Table 8.11 i n DM section, p. 291). The International Myositis Assessment and Clinical Studies (IMACS) G roup published guidelines in 2005 for the conduct of clinical trials in myositis. Consensus was Genetic factors Candidate gene studies have demonstrated HLA- DRB1*0301 and DQA1*0501 to be associated with the development of myositis, especially in patients with anti- synthetase antibodies. Possession of the TNF-308A allele has also been shown to be a risk factor for i n \202 ammatory myositis in a UK adult population. PM and DM appear to be genetically diff erent diseases, and work is ongoing to clarify these distinctions. Environmental Despite many proposed viral triggers, for example, cock- sackie, in \202 uen za, parain \202 uenza, parvovirus and cytomega- lovirus, PCR studies have failed to demons trate evidence of viral genetic material in muscle biopsy samples. Never- theless, retrovir uses, such as HIV or HTLV-1 have been associated with PM and IBM. Similar to retrovirus-neg ative PM, clonal expansion of subpopulations of CD8 positive (CD8+) T-cells is seen in thes e patients. Immunopathology HLA class I up-regulation One of the earliest features of PM is ubiquitous expression of major human leucocyte antigen (HLA) class I antigens on muscle \201 bres, e ven in areas remote from sites of in \202 am- mation. HLA class I is not normally expresse d on myo \201 bres CHAPTER 8 Autoimmune connective tissue diseases 283 \200 and this widespread up-regulation is typical of PM and IBM, but is not usually seen in othe r chronic myopathies or dystrophies. Exclusion of differential diagnoses. Assessment for extra-muscular involvement. Evaluation of muscle function \200 T cell cytotoxicity CD8+ cytotoxic T cells surround HLA class I expressing myo \201 bres, and contain perforin and granzyme granules, which induce muscle cell necrosis. Subsets of t hese autoin- vasive T cells are clonally expanded, presumably in response to certain antige ns present in muscle tissue. Muscle wasting is not usually seen at the outset, but may be evident in long-standing disea se. On sitting up from supine, the head may lag behind in neck \202 exor weakness. May ha ve dif \201 culty raising the arms above the head. May be unable to stand from sitting or rise from a crouching position without using arms to assist. Grade muscle power against res istance (see manual muscle testing below). Test proximal and distal groups of upper and low er limbs to determine pattern of weakness. \200 B cell involvement: B lymphocytes have traditionally been considered to play a less importa nt role in PM than in DM and in \202 ammatory in \201 ltrates in PM typically contain ver y few B cells. However, autoantibodies are present in 60-80% of patients with PM suggesting involvement of a humoral autoimmune response. Recent studies have supported this, demonstr ating large numbers of CD138+ plasma cells in muscle in PM and IBM. In addition, B cell dep letion with rituximab has been reported effective in refractory PM. Exclusion of differential diagnoses The presence of cutaneous features characteristic of de rmatomyositis should be excluded. \200 Neurological examination is essential. Key features to note include: \200 \200 Endoplasmic reticulum stress It has been postulated that, in conjunction with T-cell medi- ated cytotoxicity, there may be concurrent non-immune muscle \201 bre destruction due to an endoplasmic reticulum (ER) stress response. This could, in part account for the poor cor relation between the extent of in \202 ammatory in \201 ltrates on muscle biopsy and the degree of muscle weakness. \200 sensation is normal; deep tendon re \202 exes are preserved unless muscle atrophy is sever e; eye movements are normal (differentiates from myasthenia gravis); fasciculations are not a feature (suggest motor neuron disease). \200 The ER usually processes, folds, and exports proteins, including HLA class I molecules. The stress response occurs due to a discrepancy between the load of proteins in the ER and its ability to process them. Major components of the ER stress response pathways are highly ac tivated in myositis. Furthermore, over- expression of HLA class I molecules has been shown to induce an ER stress response in a mouse model. ER stress results in accumulation of misf olded HLA glyc- oproteins and up-regulation of nuclear factor B and HLA class I molecules , which may perpetuate the in \202 am- matory response. The mechanisms by which this may m ediate muscle \201 bre damage have not been established. Assessment for involvement of other organs. Full cardiovascular, respiratory and joint exam inations should be performed. Fine bi-basal crepitations may indicate ILD. Co-morbidities Constitutional symptoms Fatigue, anorexia, fever and weight loss are seen in around 40%, more commonly in those with anti-synthetase antibodies. Joint disease Arthritis is associated with anti-synthetase antibodies. It is typically symm etrical and non-deforming involving wrists, hands, and knees. Arthralgia is common. Clinical features Key features in history Myopathic muscle weakness \200 \200 Pulmonary disease \200 Weakness of chest wall and diaphragmatic muscles can lead to exertional dyspnoea. In severe disease, especially in those with an acute presentation, patients may progress to respirat ory failure. Pharyngeal and oesophageal striated muscle weakness lead to dysphagia in aroun d 30% of patients with conse- quent risk of aspiration pneumonia. Dysphonia is a less commo n manifestation. Interstitial lung disease (ILD) affects approximately 30% of patients with PM/DM. Estimates vary widely and are increasing as the sensitivity of diagnostic tests imp roves. ILD is frequently subclinical and in a study screening all newly diagnosed patients with PM/DM, 65% had evidence of ILD. Typical features of ILD include cough and dyspnoea. Th e spectrum of disease ranges from asymptomatic to severe, rapidly progressive respiratory f ailure and death. Prognosis of ILD is unrelated to the severity of myositis and may develop at any stage, but is present at diagnosis of myositis in most affected patients. ILD assoc iated with PM is strongly associated with anti-synthetase antibodies. Over 70% of anti-Jo1 positive patients develop ILD. Insidious onset of weakness over weeks to months. Predominantly affects proximal muscles an d is typically symmetrical. Acute onset with early respiratory muscle involvement is occasi onally seen, but is rare. Dif \201 culty with activities, such as rising from a chair, cli mb- ing steps, and brushing hair. Fine motor movements, which rely on distal muscle strengt h, such as writing, are not usually affected until late in disease. Involvement of neck \202 exors and extensors results in dif \201 culty holding the head up. Weakness is typica lly painless. Myalgia occurs in only around 30% and is rarely severe. External ocular muscl es are involved. Key features on examination Examination should incorporate: \200 Evaluation of muscle function by observation of speci \201 c activities and direct testing of power against resistance (see below). POLYMYOSITIS 284 There is no clear guidance as to when and how frequently patients should be investigated fo r ILD. It has been advocated that all patients should be screened at diagnosis of PM as ear ly intervention may improve outcome. Baseline LFTs and U&E are essential prior to starting immunosuppressive treatments. Exclude differential diagnoses: TFTs, bone pro \201 le and vitamin D level are essential. LH, FSH , and testosterone may be indicated in males. Genetic testing may be helpful in certain cas es if an inherited muscular dystrophy or myopathy is suspected Cardiovascular disease \200 \200 Clinically overt cardiac involvement is relatively rare. Subclinical disease affects up to 75% of patients, predom- inantly manifest as abnormalities on ECG. The most common clinical ly signi \201 cant cardiac manifes- tations are myocarditis, arrhythmias, atrioventricular conduction block and congestive cardiac failure. Coronary artery disease is also frequentl y seen. Cardiac involvement is associated with increased mortality and has been reported to be the commonest cause of death in myositis patients. A 16 times increased death rate from myocardial infarction has been reported in myositis patients compared to the general popul ation. The increased cardiovascular risk may be due to a com- bination of factors including direct involvement of the heart by the myositis disease process, chronic systemic in \202 ammation and side effects of treatment. Muscle enzymes Creatinine kinase (CK) is almost always elevated in active PM and may be as high as 50 times the upper limit of the reference interval. \200 Other muscle enzymes [lactate dehydrogenase (LDH), aldolase, aspartate transaminase (AST) a nd alanine transaminase (ALT)] may also be raised. These are less sensitive than CK, but me asurement of two muscle enzymes is advocated when monitoring disease. It is imperative to c onsider other causes of raised muscle enzymes, including muscle trauma, e.g. following intr a- muscular injections or needle stimulation during EMG (CK may be elevated for up to a mon th afterwards), exercise, hypothyroidism, and medications. Auto-antibodies ANA is positive in up to 80% of cases of PM. \200\230Myositis- speci \201 c antibodies \200\231 or \200\230myositis associated antibodies \200\231 are present in a round 50%. The former occur solely in myositis but the latter may be seen in other connecti ve tissue diseases in the absence of myositis. \200 Malignancy \200 There is an increased risk of malignancy in DM, but the association with PM is less clearly established. Increased incidence of several cancers has been reported in PM, including lun g cancer, non-Hodgkin \200\231s lymphoma, and bladder cancer. However, the overall increase d risk of malignancy is modest. Estimated cancer incidence in PM is approxi- mately 1.7 \200\2232 times that of the general population. The risk of malignancy is greatest within t he \201 rst year following diagnosis and returns to normal by 5 years. Case ascertainment bias as a result of increased surveil- lance may therefore account for much of the purport ed association between PM and malignancy. However, it has been reported that cancer risk is increased in years preceding the diagnosis of myositis. Myositis speci \201 c antibodies are present in around 30% of patients. The three main cat egories are: \200 Anti-synthetase antibodies. Anti-Jo-1 is the most common. These are directed against aminoa cyl tRNA- synthetases and are found in about 20 \200\22330% of patients with PM/DM. They ar e strongly associated with the Anti-synthetase syndrome. Antibodies to the signal recogniti on particle (anti-SRP), which is required for translocation of proteins into the ER. Anti-S RP antibodies are found almost exclusively in PM and are associated with acute, severe dise ase with a very high CK and a necrotizing pattern on muscle biopsy. Antibodies to Mi-2, a n uclear helicase, are classically associated with DM, rather than PM. Anti-synthetase syndrome \200 \200 Affects up to 30% of patients with PM. Clinical features include ILD, constitutional sympto ms, Raynaud \200\231s phenomenon, mechanic \200\231s hands (roughening and cracking of the skin of the \201 ngers), and arthritis. Anti-synthetase antibodies are present, most comm only anti-Jo-1. However, similar features may be seen in patients with other antibodies, e. g. anti-PM/Scl. Myositis associated autoantibodies include anti-Ro, anti-La, anti-Sm, or anti-RNP, and sugg est the myositis is associated with other connective tissue diseases. Anti-Ku and anti-PM-S cl occur in patients with overlapping features of myositis and systemic sclerosis. Imaging Magnetic resonance (MR) imaging MR imaging is highly sensitive for muscle in \202 ammation and oedema, and is best demonstrated on fat-suppressed T2-weighted and STIR images . T1-weighted images demon- strate fatty in \201 ltration and muscle atrophy signifying es tab- lished muscle damage. \200 Associations PM occurs in conjunction with other autoimmune connec- tive tissue diseases in cluding systemic sclerosis (SSc), sys- temic lupus erythematosus (SLE), Sj gren \200\231s syndrome (SS), rheumatoid arthritis (RA), and mixed connective tissue disease (MCTD). Less commonly, it may be associated with other autoimmune conditions, such as primary biliary ci rrhosis and autoimmune thyroiditis. Roles for MRI include identifying a site for muscle biopsy (given that muscle involvement i s frequently patchy), distinguishing active myositis from muscle damage and monitoring resp onse to treatment. Magnetic resonance spectroscopy (MRS) measures met- abolic changes in mu scle and is a promising technique for monitoring disease activity, but is not widely availa ble. Investigations Laboratory tests General \200 \200 FBC may show anemia or thrombocytosis. ESR and/or CRP are elevated in 50%. CHAPTER 8 Autoimmune connective tissue diseases 285 Elevation of troponin I is a relatively cardiac speci \201 c and is found in suspected myo carditis; however, won \200\231t discriminate cardiac lesions. Other frequently used marker s of myocardial damage, such as troponin T and CK-MB, are less cardiac speci \201 c, and m ay be elevated due to skeletal muscle in \202 ammation. Further specialized imaging, e.g. scintigraphy or MR, may be indicated in suspected myocarditis. Endomyocardial biopsy is rar ely necessary. Ultrasound (US) US is less sensitive for muscle in \202 ammation than MR; however, it has the advantages of being cheaper and more easily available. Assessment of muscle blood vesse l \202 ow with color \202 ow Doppler may have a role in monitoring myositis activity. Histology \200 Muscle biopsy is mandatory to con \201 rm the diagnosis and exclude other conditions, whic h can mimic PM. The histological hallmark of PM is endomysial in \202 amma- tory in \201 ltrates of CD8+ T lymphocytes surrounding non- necrotic muscle \201 bres expressing HLA c lass I molecules. A key feature is that the muscle \201 bres appear histologi- cally heal thy. This distinguishes the primary in \202 ammation of PM from inflammation secondary to myofibre damage, which may be seen in other myopathies. Muscle pathology can be patchy and repeat biopsy may be required if the \201 rst is inconclusive. Screening for malignancy An extensive, blind search for malignancy is not recom- mended. Ba seline evaluation at diagnosis of PM should include: \200 Thorough history and examination, including lymph nodes, breast and rectal examinations. CX R and urinalysis. FBC, urea, electrolyte, and creatinine, LFTs, bone pro \201 le, and both serum and urine protein electrophoresis. Pelvic examination and cervical smear in women. P SA in men. Consider colonoscopy, mammogram, abdominal and pelvic US, and, if suspicion stil l high, whole body CT. \200 \200 \200 Other investigations Electromyography (EMG) EMG is abnormal in 90% of patients and is usefu l for excluding neurogenic disorders and assessing disease activity. However, the \201 nd ings are non-speci \201 c and do not differentiate PM/DM from other myopathies. \200 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.