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 Measuring peak \202 ow is an easy bedside test to monitor for deterioration if spirometry is not easily available. Formal lung function with spirometry and diffusion capacity shoul d be performed at time of diagnosis. Additional investigation is based on risk and age appr opriate screening tests (such as mammography). Differential diagnosis Mimics of DM should be considered. Although rare, para- neoplastic s yndromes should be considered, but also: Imaging Radiographs, mammography, US and CT Given the association of DM with malignancy, CX R is essential. An indiscriminate search for malignancy is not recommended. \200 Drug or toxic myopathies A number of drugs, including glucocorticoids (GCs), cause proximal myopathy. \200 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*, clo \201 brate, statins, salbutamol, penicillin, colchi- cine, D-penicillamine*, sulphonamides , hydralazine, ciclosporin, phenytoin, cimetidine* (muscle cramps), zidovudine, carbimazole , and tamoxifen. Compared with DM, in steroid myopathy the CK is normal and biopsy is consi stent with non-in \202 ammatory \201 bre atrophy. GC-induced myopathy should be consid- ered during GC treatment, especially if there is no response to treatment. The use of ultrasound (US) and CT will need to be considered depending on clinical assessme nt and the need to focus on identifying any potential malignancy. MR demonstrates areas of muscle inflammation by evaluating the presence or absence of muscle oedema. The most common ly used MR modalities for skeletal muscle imaging include T1- and T2-weighted, proton densi ty, and STIR sequences. T1-weighted images help to differentiate skeletal muscle from fat, while T2-weighted images and STIR are useful for the detection of oedema. CHAPTER 8 Autoimmune connective tissue diseases 293 Macro-CK may be a normal variant, but can be produced in association with malignancy. A scr een for tumors may be necessary. CK can be elevated secondary to muscle trauma. If modest e levations in CK are thought to arise from trauma, a delay before re-testing is prudent. CK can be very modestly (but signi \201 cantly and persistently) elevated in sarcoid myopathy . The myositis occurring 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. proton pump inhibitors and quinolone antibiotics. Alcohol in excess and some il legal drugs (e.g. ecstasy) are associated with severe toxic myopathy occasionally resulting in rhabdomyolysis. Disease activity assessment and monitoring Clinical assessment should be based on evaluatin g changes in several muscle groups and these same groups should be tested at each review. M uscle strength represents one of the most sensitive parameters for monitoring disease activ ity, and needs to be scored between zero and \201 ve for standardization. Isokinetic test ing with dynamometers, if available, are more sensitive than physical examination and can b e used to measure and monitor muscle strength objectively (e.g. using a Cybex dynamometer). Treatment Objectives of management The goals of treatment are to improve muscle strength, prevent muscle loss, improve skin disease, avoid glucocor- ticoid-induced myopathy by using judicious doses of GCs, and prevent extra muscular manifestations. Treatment should begin immediately following diagnosis. Endocrine myopathies Hypothyroidism mimics in \202 ammatory myopathy. Distin- guishing fea tures are the subacute onset of muscle weakness and abnormal thyroid function tests. Metabolic myopathies Caused by disorders of carbohydrate and lipid metabolism, they can be distinguished from DM clinically by the inter- mittent nature of the attacks of acute muscl e pain and tenderness, usually induced by exertion. Infectious myositis Viral and parasitic infections may cause diffuse muscular involvement w ith a subacute or chronic course. \200 Bacterial myositis tends to be localized and has a fulminant presentation. Myositis can be the presenting feature of HIV disease. In HIV-positive patients, infections causing muscle disease include MTB and microsporidia. Physical therapies Early rehabilitation and physiotherapy (PT) are necessary to prevent con tractures and improve muscle function. Muscular dystrophies These conditions are an inherited group of progressive myopathic disor ders where an increase of CK, electodiag- nostic studies, and biopsy \201 ndings may be s imilar to DM. They can be distinguished from DM, however, by the posi- tive family history and relatively early insidious onset and slow progression. Exercise regimens should be tailored to the severity of weakness. Wheelchair or bed-bound p atients should still receive passive range of motion exercises, and may bene \201 t from h eat and massage prior to therapy Non-pharmacological skin management \200 Patients should be advised regarding protection from the sun and the importance of applying broad sunscreens There is no effective medical treatment for calcinosis and controlled tri als are lacking. Aluminum hydroxide antacids, diltiazem, probenecid, and colchicine can be tri- alled but often provide less than ideal results. Surgical therapy may be required for localized calci \201 c deposits that interfere with joint function or are painful, but is usually a last resort If the deposits are infected or discharging than surgical interventio n is required Other in \202 ammatory myositis \200 In chronic sarcoid some evidence for muscle in \202 ammation is not uncommon with raised C K fairly typical. Indeed, in biopsy studies, there is evidence for sarcoid granulomata in a substantial number of patients with the diagnosis. However, many patients are asymptomatic and have no obvious or mild muscle weakness. Myasthenia gravis can present insidiously, of ten with variable weakness during the day (fatiguability is a key feature, which may be mor e noticeable in its effect towards the end of the day). Immunosuppression Glucocorticoids (GCs) are used initially and are used \201 rst line to establish disease control. A number of immunosup- pressants can be used in a \200\230stero id-sparing \200\231 role (second-line agents). It is logical to commence the second-line ag ent at the outset to reduce the cumulative dose of prednisolone. Other conditions An appreciation of some conditions that can present with widespread pain, and either frank or perceived weakness is important. The following should always be conside red in these cases: Guillain \200\223Barre syndrome, myelopathic lesions, extensive SpA-rel ated polyenthesopathy (usually psoriasis- related), and \201 bromyalgia. Glucocorticoids (GCs) The usual initial dose of prednisolone is 1 mg/kg per day up to a max imum dose of 80mg/day. \200 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. It is important to be aware of that production of macro- CK can present with elevated routine CK results. In more severe cases pulse methylprednisolone may be given at 1 g/day on 3 consecutive days . There is nothing in the literature on lower doses of pulse methylpred- nisolone, but indi vidual factors need to be taken into account such as age, co-morbidities, etc. High dose or al GCs are continued for up to 6 weeks then should be tapered, but in light of clinical pro gress and use of GC-sparing drug use. DERMATOMYOSITIS 294 Complications of GC therapy inevitably occur with the high doses and long duration of treat ment necessary. Ensuring patients are replete in vitamin-D (25OHD) and avoiding secondary h yperparathyroidism, if necessary with supplements, is important. A regular bisphosphonate i s recommended (UK Royal College of Physicians Guidelines 1999/2000) for all patients \211 65 years old treated with GCs and for younger patients with hip or spine T-score (DXA scan) \211 \200\2232.5). Anti-CD20 chimaeric monoclonal antibody (Rituximab) In a number of small case series, impro vement in muscle strength has been seen with Rituximab as early as 4 weeks after the initia l infusion with cutaneous disease improving within 12 weeks. The optimal dose has yet to be deter- mined. Rituximab is more likely to lead to prolonged disease control than IVIG. Other immunosuppressive therapeutic options \200 Ciclosporin has the same ef \201 cacy as MTX and is useful in those cases with ILD, and in combination with MTX for refractory DM. Tacrolimus has been used in those with refractory in \202 ammatory myositis complicated by ILD, there have been small case series reported i ndicating ef \201 cacy of tacrolimus in improving muscle strength and respiratory function . Applied topically, it is effective on cutaneous lesions. Mycophenolate mofetil has been u sed with some success in resistant myositis, evidence is emerging of it \200\231s ef \201 cacy on both the myositis and dermatological fea- tures. It has a slow onset of action. Dos es of 2 g daily are effective and it is useful as a steroid-sparing agent. Cyclophosphamide can be effective though given the side effect pro \201 le its use should be reserved for those with aggressive disease or associated severe ILD. Anti-TNFA therapies have been used with mixed results in DM. Convincing data that they are ef \201 cacious overall is lacking . AZA and MTX combination therapy is a further option, but treatment-related morbidity is a risk. Azathioprine (AZA) Azathioprine (AZA) is usually initiated at a dose of 50 mg/day. If toler ated the dose may be increased to 150 \200\223200 mg/day to a maximum of 2.5 mg/kg/day. \200 Before beginning AZA, screening for low thiopurine methyltransferase activity is recommende d. AZA is preferable to methotrexate (MTX) in those with associated ILD, heavy alcohol use or underlying liver disease, where MTX is relatively contra-indicated. Methotrexate (MTX) Methotrexate is administered in doses of 15 \200\22325 mg/week with foli c acid 5 mg/week the day after MTX. \200 It is often preferred to AZA due to its favorable dosing regimen and earlier bene \201 t. At doses greater than 15 mg/week subcutaneous or intramuscular administration should be con sidered. GC, AZA, and MTX Therapy duration There are no clear guidelines on the optimal duration of therapy. A typical course of GCs lasts 9 \200\22312 months and the \200\230steroid-sparer \200\231 continued for longer. \200 Once remission has been achieved the \200\230steroid-sparer \200\231 should be tapered wit h a view to cessation after a further 6 months. Response to treatment is variable \200\223 with some patients showing improvement within weeks, while others take months. When cutane ous \201 ndings are refractory to systemic treatment topical tacrolimus or antimalarial t herapies, such as hydroxychloroquine may be of bene \201 t. Failure of DM to respond to GC s with AZA or MTX requires treatment with third line agents (see below). However, limited e vidence for the ef \201 cacy of treatments given for resistant DM exists. Failure to respo nd also prompts reassessment of the diagnosis. Relapse (of muscle or skin disease) \200 Relapse after de \201 nite disease control requires either an increase or recommencement o f prednisolone at the lowest dose required to establish disease control. If the relapse is severe, pulse methylprednisolone therapy (of up to 1 g daily for 3 days) or high dose oral GCs (1 mg/kg to a maximum 80 mg) should be used. Immunosuppressant dose should be maximized and if disease control is still not achieved, agents for refractory disease should be used . Reconsideration of the diagnosis or iatrogenic causes of myopathy (steroid) should be ass essed Other issues regarding treatment with immunosuppression Owing to use of high dose GCs and i mmunosupression, patients are at risk for opportunistic infections. \200 Intravenous immunoglobulin (IVIG) There have been two small controlled trials, one of which was a double-blind randomized controlled-trial (RCT) in- volving exclusively patients with DM. Improvement in both muscle and skin became noticeable after the \201 rst infusion. \200 The bene \201 t of IVIG is usually short-lived. Repeat infu- sions are needed althou gh there have been reports of patients having sustained responses for up to 3 years. The us ual IVIG regime is 2 g/kg/monthly for 4 \200\2236 months. In the acute setting IVIG may be used in a dose of 0.5 \200\2232 g/kg daily for 3 \200\2235 days. There is no evidence for r elative ef \201 cacy of the different IVIG preparations. Vigilant monitoring is required at each review for signs and symptoms of infection. Pneumoc ystis jiroveci prophylaxis with co-trimoxazole should be considered in patients requiring h igh dose GCs and immunosuppressants. Patient advice \200 All patients should be advised regarding healthy lifestyle including no smoking and moderat e alcohol intake. Patients should be advised about the risk of infections and taught how to measure their own temperature. Live vaccinations should not be given. Yearly in \202 uenz a vaccine should be given (and pneumococcal vaccine status brought up to date) for those on immunosup- pressants. Plasmapheresis Plasmapheresis has no proven ef \201 cacy compared with placebo in double-b lind RCTs. CHAPTER 8 Autoimmune connective tissue diseases 295 Advice about: the treatments, GC-induced osteoporosis, and the need to be vigilant about po ssible evolving malignancy need to be given. Patient organizations www.myositis.org.uk Other Internet sites Arthritis research campaign website provides useful infor- mation abou t arthritis for health professionals and patients. Available at: www.arc.org.uk; American C ollege of Rheumatology website has extensive resources including information on conditions for mem- bers and patients. Available at: www.rheumatology.org/ Other Patients with dysphagia and/or dysphonia should be referred to a speech therapist for advice regarding dietary guidance (considering aspiration risk). Prognosis Serum CK does not predict the course of disease or response to treatment, but sho uld be used as a guide for management decisions. The clinical and laboratory features assoc iated with a poor prognosis include: \200 \200 \200 \200 \200 \200 \200 \200 \200 ICD10 codes M33.1 M36.0 M33.9 Dermatomyositis; Dermato(poly)myositis in neoplastic disease; Dermatopolymyositis. Older age at onset. Severe weakness at presentation. Dysphagia. Respiratory muscle weakness . Interstitial lung disease. Associated malignancy. Calcinosis. Presence of anti-Jo-1 antib ody. Anti-SRP antibodies. See also: Polymyositis Metabolic myopathies Eosinophilia myalgia syndrome Inclusion body my ositis p. 282 p. 522 p. 520 p. 302 References Bohan A, Peter J. Polymyositis and dermatomyositis (Part 1). NEJM 1975; 292: 344 \200\2237. Bohan A., Peter J. Polymyositis and dermatomyositis (Part 2) NEJM Current controversies Aetiological hypotheses and diagnostic issues \200 1975: 292: 403 \200\2237. Briani C, Doria A, Sarzi-Puttini P, Dalakas M. Update on idiopathic in \202 ammatory myopathies. Autoimmunity 2006; 39(3): 161 \200\22370. There is still much to be learned about the pathogenesis of DM \200\223 the genetic, envir onmental factors, and the exact role of MSAs. With further understanding, speci \201 c imm unotherapies can be formulated. The exact incidence of DM is dif \201 cult to ascertain, a s there are few published epidemiological studies and pre- vious data are based on old stud ies using unvalidated diagnostic criteria. No formally validated classi \201 cation criter ia or assessment tools are available for clinical use. The direct relationship of inflammat ory myositis to malignancy is still not understood, although there does appear to be a caus al relationship. Controversy exists regarding the extent of screening for malignancy in a n ew diagnosis of DM. The role of muscle US in evaluating extent and location of in \202 amm ation. Buchbinder R, Forbes A, Hall S, et al. Incidence of malignant disease in biopsy-proven in \202 ammatory myopathy. Ann Intern Med 2001; 134: 1087 \200\22395. Callen J. Dermatomyositis. Lancet 2000; 355: 53 \200\2237. Cherin P, Pelletier S, Teixeira A. Results and long term follow up of intravenous immunoglobulin infusions in chronic refra ctory poly- myositis: an open study with thirty- \201 ve adult patients. Arthritis Rheum 2 002; 46: 467 \200\22374. Chinoy H, Salway F, Fertig N, Shephard N. In adult onset myositis, the presence of intersti tial lung disease and myositis speci \201 c/ associated antibodies are governed by HLA Cla ss II haplotype, rather than myositis subtype. Arthritis Res Ther 2006; 8: R13. Choy E, Hoogendijk J, Lecky B. Cochrane Database Syst Rev 2005; 3: CD003643. Cordeiro A, Isenberg D. Treatment of in \202 ammatory myopathies. Postgrad Med J 2006; 82: 417 \200\22324 Dalakas M. Polymyositis, dermatomyositis, and inclusion-body myositis NEJM 1991; 325: 1487 \200\22396. Dalakas M, Hohlfeld R. Polymyositis and dermatomyositis. Lancet Therapy issues \200 2003; 362: 971 \200\22382. The superiority of high-dose GC versus immunosupressant plus high-dose GC initially. There is a lack of high quality RCTs with therapeutic agents in DM making decisions regarding app ropriate \201 rst and second line therapy less clear. There are no trials comparing AZA w ith MTX as steroid- sparing agents in DM. Decisions are based on patient pro \201 le and p hysician preference. There is a lack of international or national guidelines on management of DM. Dalakas MC, Illa I, Dambrosia JM. A controlled trial of high- dose intravenous immune globu lin infusions as treatment for dermato- myositis. NEJM 1993; 329: 1993 \200\2232000. Dinh HV, Mc Cormack C, Hall S, Prince HM. Rituximab for the treatment of the skin manifesta tions of dermatomyositis: a report of 3 cases. J Am Acad Dermatol 2007; 56: 148 \200\22353. Efthimiou P, Schwartzman S, Kagen L. Possible role for tumor necrosis factor inhibitors in the treatment of resistant dermato- myositis and polymyositis:a retrospective study of eigh t patients. Ann Rheum Dis 2006; 65: 1233 \200\2236. Greenberg.A gene expression approach to study perturbed pathways in myositis. Curr Opin Rheum 2007; 19: 536 \200\22341. Resources Assessment tools Muscle strength testing using Medical Research Council (MRC) sca le graded from zero (which is the lowest) to \201 ve (the highest). HAQ questionnaire wid ely used generic instrument assess- ing self-reported patient-orientated outcome measures. Greenberg S. Proposed immunologic models of the in \202 ammatory myopathies and potential therapeutic implications. Neurology 2007; 69: 2008 \200\22319. Iannone F, Scioscia C, Falappone PC. Use of etanercept in the treatment of dermatomyositis: a case series. J Rheumatol 2006; 33: 1802 \200\2234. Kuo G, Carrino J. Skeletal muscle imaging and inflammatory myopathies. Curr Opin Rheumatol 2007; 19: 530 \200\2235. Guidelines No published society guidelines. Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis Rheum 2005; 52: 601 \200\2237. DERMATOMYOSITIS 296 Noss EH, Hausner-Sypeck Dl, Weinblatt ME. Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol 2006; 33: 1021 \200\2236. Mastaglia FL,Phillips BA. Idiopathic inflammatory myopathies: epidemiology, classification, and diagnostic criteria. Rheum Dis Clin N Am 2002; 28: 723 \200\22341. Saito E, Koike T, Hashimoto H, et al. Ef \201 cacy of high dose intrave- nous immune globu lin therapy in Japanese patients with steroid resistant polymyositis and dermatomyositis. M od Rheum 2008; 18: 34 \200\22344. Medsger TA, Dawson WN, Masi AT. The epidemiology of polymy- ositis. Am J Med 1979; 48: 715 \200\22323. Mimori T, Yoshitaka I, Nakashima R, Yoshifuji H. Autoantibodies in idiopathic in \202 amma tory myopathy: an update on clinical and pathophysiological signi \201 cance. Curr Opin Rh eum 2007; 19: 523 \200\2239. Neri R, Mosca M, Stampacchia G, et al. Functional and isokinet ic assessment of muscle strength in patients with idiopathic in \202 am- matory myopathies . Autoimmunity 2006; 39(3): 255 \200\2239. Therapeutic Guidelines Rheumatology. 2006 Rheumatology Expert Group. North Melbourne: Therapeutic Guidelines Ltd. This page intentionally left blank JUVENILE DERMATOMYOSITIS 298 Juvenile dermatomyositis De \201 nition Juvenile dermatomyositis (JDM) is one of a number of juvenile idiopathic in \202 ammatory myopathies (JIIMs). JIIMs are rare and JDM is by far the commonest. There i s a decreasing occurrence in juvenile polymyositis, amyopathic dermatomyositis, overlap myo sitis and inclusion body myositis (IBM). The reader is referred to more detailed texts for further information on these other rare JIIMs (Compeyrot-Lacassagne & Feldman, 2007). JDM d iffers from the adult form in a number of ways: \200 Vasculitis is frequent and often sev ere. \200 Calcinosis is common, especially in the recovery phase. \200 Polymyositis is uncommon. \200 Malignancy is very rare. HLA-DMA*0103 and HLA-DMB*0102 alleles are more frequent in JDM. Maternal microchimaerism (t he persistence of maternal blood cells transferred by the placenta during fetal development ) has been implicated and might induce a graft-versus-host type response. Environment Moderately high frequencies of infectious symptoms are found at onset suggestin g an infectious trigger. Clinical features Key features in the history Most children present with insidious onset di sease, whereby the rash precedes obvious muscle weakness by months. \200 Diagnostic criteria The diagnosis is based on the characteristic JDM rash and proximal musc le in \202 ammation. The diagnostic criteria were originally proposed by Bohan and Peter a nd have not been superceded (Bohan, 1975). \200 A few children present with an acute onset illness characterized by fever, prostration, ras h, and profound weakness. Diagnosis is frequently delayed, and the rash is attributed to in fection or allergy. Muscle pain and arthralgia are common. Subtle signs of muscle weakness must be sought in the history, such as: \200 In pediatric patients a diagnosis of JDM requires the presence of the pathognomonic rash an d two of the other criteria. Polymyositis is considered probable with three of the criteria (no rash). Muscle appearances on MR may be suf \201 ciently reliable to become part of th e diagnostic criteria for JDM in future (Brown et al., 2006). \200 a refusal to use the potty (dif \201 culty getting up from squatting); a refusal to use th e school bus (dif \201 cultly with the high \201 rst step); struggling to brush hair. Sometimes the child \200\231s actions are put down to behav- ioural problems, particularly as the children are often in pain and become increasingly frustrated. Diagnostic criteria for juvenile dermatomyositis Cutaneous lesions consisting of heliotrope (lilac) disco- louration of the eyelids with periorbital oedema and an erythematous scaly rash over the dorsal aspects of the metacarpophalangeal and proximal interphalangeal joints (Gottron \200\231s sign) Key features on examination Skin The \201 rst sign of the rash is often swelling of the e yelids and supraorbital areas. \200 \200 + any 2 from: Symmetrical and progressive proximal muscle weak- ness ( dysphagia or respi ratory muscle involvement). Elevation of the serum level of one or more of the following sk eletal muscle enzymes: creatine kinase (CK), aspartate aminotransferase (AST), lactate dehy drogenase (LDH) or aldolase (ALD). Electromyographic (EMG) demonstration of the characteris tics of myopathy and denervation. Muscle biopsy documenting histologic evidence of necrosis and in \202 ammation. A heliotrope hue to upper eyelids evolves. A mild eruption on the face follows, typically e xtending down the nasolabial folds. An erythematous or violacious maculopapular eruption ap pears over the extensor surfaces of the PIP joints, elbows, and knees. The erythematous pla ques over the PIPJs (Gottren \200\231s papules) can atrophy. Nail cuticles become erythemat ous owing to periungual vasculitis (the nail-fold capillary vessels show thickening, tortuo sity, dropout, and thrombosis seen under the microscope). Muscles and joints \200 Epidemiology A survey in the UK in 1995 suggested an incidence of 1.9 per million children below the age of 16 years. In the USA, between 1995 and 1998, data suggested an incidence o f 3.2 per million children below 17 years. There does not seem to be an ethnic difference. Mean age of onset was 6.8 years in the UK survey with 5:1 girls to boys. One characteristic suggestive sign of muscle weakness is dif \201 culty with prolonged ele vation of the head whilst supine. An inability to do an unassisted sit up and Gower \200 \231s sign (an inability to rise from the \202 oor without using the hands to \200\230cl imb up \200\231 the legs) are reliable signs of truncal and proximal leg muscle weakness, r espectively. Dysphagia (palatal muscle weakness) is common with more severe presentations a nd a nasal speech pattern may develop. These children are at risk of aspiration pneumonia. Etiology and pathogenesis Genetic \200 HLA-DQA1*0501 is associated with JIIM in several ethnic groups. CHAPTER 8 Autoimmune connective tissue diseases 299 Weakness of respiratory muscles and impaired ability to increases the risk of aspiration pn eumonia. About 60% of JDM patients have in \202 ammatory arthritis, two-thirds having an o ligoarticular pattern of arthritis and a third, polyarticular. Many children have a \202 itting or migratory arthralgia. In insidious onset disease, joint contractures can develop and need to be discriminated from any limitation of joint movement owing to arthritis. Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), and both physic ian and patient global assessments of disease and skin activity. Most tools are available a t the NIH website (see Resources below). \200 Measurement of height, weight, and pubertal status should be done regularly. The CMAS asses ses function, as well as muscle strength, and is validated for use in children with JIIMs t o serially measure the child \200\231s proximal muscle power. Nail-fold capillaries should be examined for infarcts. Contractures, arthritis, and calcinosis assessed. Serial MR scans of proximal muscle may be helpful in assessing ongoing in \202 ammation in the absence of other markers of activity. \200 \200 \200 Other \200 Co-existent \201 brosing alveolitis may be under-diagnosed. Chest auscultation and simple spirometry should be undertaken. Visceral vasculitis occurs in a minority of children, wit h abdominal pain, GI bleeding, and perforation. Dystrophic calcification occurs in about 40 %, often within 6 months of onset of the disease. Calcinosis is seen as super \201 cial pl aques or nodules, or as deep tumorous deposits in muscle or in the inter-muscular fascial p lane. Subcutaneous calcinosis can erupt sometimes discharging in ulcerated skin lesions. It may occur during the healing phase of the disease. Lipodystrophy \200\223 generalized or partial loss of subcutaneous fat; occurs in a minority of children. Treatment Objectives of treatment Induction of remission of the inflammatory disease, preve ntion of loss of muscle bulk and strength, controlling skin disease, and minimizing the sid e effects of immunosup- pression long-term. Ensuring adequate growth and devel- opment, mai ntaining progress at school, and social development through the input of a multidisciplinar y care team is of obvious importance. Physical therapies Dedicated pediatric physiotherapy is a key component of retaining muscle strength once the in \202 ammatory muscle disease is controlled on medication. Investigations Laboratory \200 Immunosuppression \200 Creatine kinase (CK) may be raised, although this is not essential to make the diagnosis. I ts detection depends on at what stage of the disease it is measured. LDH, ALT, and AST are enzymes derived from both liver and muscle. GGT \200\223 a specific liver enzyme \200\223 is not elevated in myositis. ESR is not a good marker of muscle in \202 ammation and is of ten normal even in active disease. ANA is not always positive but anti-tRNA antibodies have been described (e.g. Jo-1). Von Willebrand factor, a marker of endothelial cell activa- ti on, may be useful for monitoring vasculitic complications. High dose glucocorticoids (GCs) are given (prednisolone 2 mg/kg/day in 3 divided doses) for about 6 weeks. Dose is tapered slowly depending on response. If there is a poor response t o oral GCs, or in the presence of dysphagia, dysphonia, pulmonary disease or gastrointestin al vasculitis, pulse intravenous methylpred- nisolone is given. Children need to remain rep lete in vitamin-D (de \201 ciency may evolve as children will be advised to avoid exposure of skin to the sun because of the photosensitive skin rash). Secondary hyperparathyroidism should be avoided by remaining vitamin-D replete and keeping dietary calcium intake adequa te. If DXA scanning suggests very low Z scores where fragility fractures have also occurred , then a bisphospho- nate needs to be considered to protect against GC- induced osteoporosi s. Immunosuppression, with methotrexate (MTX) 15 mg/ m2 by subcutaneous injection, is often introduced early as a \200\230steroid-sparing \200\231 strategy, despite limited publishe d evidence for its effect. Cyclophosphamide, IVIG, azathioprine and ciclosporin have been u sed for GC and MTX resistant disease, or where there is intolerance to MTX. There is notabl e trial activity in this area (see IMACS and PRINTO). Anti-TNFA is being used increasingly for persistent disease and in one notable series, infliximab has shown to be effective in r efractory JDM (see Riley et al., 2008). Rituximab (anti-CD20) trials in JDM are being under - taken under the auspices of the International Myositis Assessment and Clinical Studies (I MACS) group. Topical tacrolimus may be useful adjunctive treatment for the JDM rash. Imaging \200 Mild myositis as demonstrated by MR scanning (using fat-suppressed T2-weighted sequences) m ay be present without elevation of muscle enzymes. A CXR and pulmonary function testing wit h a check of transfer factor and then if necessary HRCT chest should be done if there is re spiratory compromise. Discriminating thoracic muscle weakness from intrinsic lung disease a s a cause of dyspnoea is key. Differential diagnoses \200 The presence of Raynaud \200\231s phenomenon should raise the suspicion of mixed connective tissue disease (MCTD) or SLE as alternative diagnoses. Post-infectious myositis (in \202 uenza A&B, cocksackie B) causes a raised CK, but usually lasts just 3 \200\2235 days. Metab olic myopathies and in \202 ammatory myositis accom- panying other autoimmune connective t issue diseases - such as Systemic Sclerosis (SSc) \200\223 need to be considered. Disease activity assessment Commonly used and validated tools for assessing disease activit y are the Childhood Health Assessment Questionnaire (CHAQ), Manual Muscle Testing (MMT), Ch ildhood Myositis JUVENILE DERMATOMYOSITIS 300