CHAPTER 13 Systemic sclerosis and related disorders 394 Scleroderma-like \201 brosing disorders Eosinophilic fasciitis \200 This is an uncommon idiopathic condition that is characterized by rapid spread of skin changes over the extremities. Skin initially takes on a \200\234peau d \200\231orange \200\235 appearance, which is replaced by induration. \200 Like SSc, \202 exion contractures and Raynaud \200\231s phenomenon may be present. Unlike SSc, the epidermis is spared (i.e., super \201 cial wrinkling of the skin is intact) and nailfold capillary microscopy is normal. \200 This condition may resolve s pontaneously. Otherwise, 70% of cases respond to corticosteroids. This condition may be a paraneoplastic phenomenon. It is overrepresented in women and in the hematologic malignancies in this respect. The paraneopl astic condition often fails to respond to steroids and resolves on successful treatment of the underlying malignancy. \200 Methotrexate or mycophenolate mofetil may be helpful, but this has not been well studied. Nephrogenic systemic \201 brosis (NSF) \200 Also known as nephrogenic \201 brosing de rmopathy, the current nomenclature re \202 ects the systemic nature of this disease, which can lead to \201 br osis in the muscles, myocardium, lungs, kidneys, and testes. NSF is characterized by the presence of skin induration, nodular plaques, and \202 exion contractures in the absence of Raynaud \200\231s phenomenon. Lesions develop over days to weeks, and initially favor the lower extremities. The majority of patients will have end-stage renal disease and a history of exposure to gadolinium-based contrast. Histologically, NSF lesions are characterized by collagen bundles surrounded by \201 broblast-like epithelioid or stellate cells and mucin deposition, whic h can extend into the fascia and muscles. \200 Response to immunosuppressive agents is di sappointing. Early institution of physical therapy to prevent contractures and muscle wasting is important. Pa in management may be especially challenging. \200 Because of precautions taken by the rad iology community, new cases of NSF have become progressively uncommon. Scleromyxedema \200 This is characterized by papular waxy induration of the skin along th e forehead (glabella), the neck, and behind the ears. Unlike SSc, scleromyxedema may also affect the middle of the back, which is generally spared in scleroderma. Scleromyxedema can be associated with esophageal dysmotility and myopathy; case reports hav e also demonstrated an association with severe neurologic sequelae, including encephalopath y, seizures, coma, and psychosis. This condition may respond to intravenous immunoglobulin(0.4 g/kg/ day for 5 days). SCLERODERMA-LIKE FIBROSING DISORDERS 395 Scleredema \200 Scleredema is a scleroderma-like disorder associated with doughy induration of the skin along the back, neck, face and chest. Unlike scleroderma, scleredema typically spares the distal extremities. \200 This disorde r is generally seen in association with poorly controlled diabetes, monoclonal gammopathy, or following certain infections, such as streptococcal pharyngitis. Prognosis depends on the underlying etiology. Scleredema that occurs after infection may re solve spontaneously. Scleredema associated with diabetes may improve with better glucose co ntrol. For some patients, ultraviolet light therapy (such as UVA-1, PUVA and photopheresis) may be bene \201 cial. This page intentionally left blank 397 Chapter 14 Idiopathic in \202 ammatory myopathies \200\224 polymyositis (PM) and dermatomy ositis (DM) Epidemiology and diagnosis 398 Clinical features of PM and DM 400 Investigation of PM and D M 404 Autoantibodies in myositis 406 Treatment of PM and DM 410 Inclusion-body myositis (IB M) 413 Inclusion-body myositis 413 PM and DM in children 414 CHAPTER 14 Idiopathic in \202 ammatory myopathies 398 Epidemiology and diagnosis \200 The idiopathic in \202 ammatory myopathies are character ized by proximal muscle weakness and evidence of autoimmune-mediated muscle breakdown. These disorders inclu de: \200 Polymyositis \200 Dermatomyositis \200 Juvenile dermatomyositis \200 Myosi tis associated with neoplasia \200 Myositis associated with connective tissue disease \200 Inclusion body myositis Polymyositis (PM) and dermatomyositis (DM) are the most common forms of idiopathic in \202 ammatory myopathy, the latter distinguished by the presence of a characteristic rash. Over lap syndromes with other autoimmune rheumatic diseases occur in 15 \200\22320% of cases. These conditions are rare. PM has an estimated incidence of 2 \200\2238 per million. Incidence increases with age and is highest between the ages of 40 \200\22365 years. The male to female ratio is 2:1, but is lower in myositis associated with malignancy , and higher during the childbearing years (5:1). A small amount of evidence suggests that the incidence in African-Americans compared to white Caucasians is 3 \200\2234:1. The uncertainty about etiology makes classi \201 cation of these conditions dif \201 cult . However, a modi \201 cation of Bohan and Peter \200\231s classi \201 cation (1975) show n in Table 14.1 serves this purpose at present. There are a number of secondary causes of myositis and myopathies. These will be discussed later in this chapter. The criteria for the diagnosis of PM and DM are shown in Table 14.2. Table 14.1 Modi \201 cation of Bohan and Peter \200\231s classi \201 cation of PM and DM 1 Primary idiopathic polymyositis 2 Primary idiopathic dermatomyositis 3 1 or 2 above, with malignancy 4 Juvenile poly(dermato)myositis 5 Overlap syndromes with other autoimmune rheumatic diseases 6 Inclusion-body myositis 7 Rarer myositis: granulomatous eosinophilic focal orbital 8 Drug-induced EPIDEMIOLOGY AND DIAGNOSIS 399 Table 14.2 Criteria for the diagnosis of poly/dermatomyositis 1 Compatible weakness. Symmetrical proximal muscle weakness developing over weeks or months 2 Elevated serum muscle enzymes, creatine kinase and aldolase 3 Typical electromyographic \201 ndings: myopathic potentials (low amplitude, short duratio n, polyphasic) \201 brillation, positive sharp waves, increased insertional activity, com plex repetitive discharges 4 Typical muscle biopsy \201 ndings 5 Dermatological features of DM: Gottron \200\231s papules, involving \201 ngers, elbows, knees, and medial malleoli Heliotrope sign around the eyes Erythematous and/or poikilodermatous rash CHAPTER 14 Idiopathic in \202 ammatory myopathies 400 Clinical features of PM and DM Myositis \200 Muscle weakness is the main clinical feature in both conditions and is almost universal, tending to develop insidiously over months but occasionally developing with great speed. The weakness is usually symmetric and diffuse, involving the proximal muscles of the neck, shoulders, trunk, hips, and thighs; the lower limb muscles tending to be clinically symptom atic \201 rst. Weakness of the distal muscles is rare but can occur late in the disease. The face and ocul ar muscles may also be involved. Shortness of breath may be a consequence of diaphragmatic and intercostal muscle weakness ( as well as other causes that will be discussed later), and should be looked for. Myalgias occur in about 50% of cases; they are usually mild and sometimes dif \201 cult to distinguish from polymyalgia rheumatica. There may be atrophy in chronic disease, more so in PM than DM, and contractures may occur in disease of long duration. Often the distinction between an autoimmune rheumatic disease overlapping with PM/DM versus an autoimmune rheumatic disease with myositis as a manifestat ion can be very dif \201 cult. The relative severity of clinical symptoms and the serologi cal picture may be of help. Cutaneous disease \200 The rash of DM commonly precedes the weakness by weeks to months. The rash may parallel the weakness or remain independent, persisting after the myos itis resolves. Erythematous or violaceous papules or plaques (Gottron \200\231s papules) or macular patches (Gottron \200\231s sign) may occur over the metacarpophalangeal and proxim al (occasionally distal) interphalangeal joints. Occasionally these lesions may be found on the extensor surfaces of the knees, wrists, elbows, or medial malleoli. The rash is presen t in up to 80% of cases. A macular eruption may involve the upper chest, neck, shoulders, extremities, face, and sca lp. This may develop into poikiloderma, hyper- or hypopigmentation with atrophy and telangi ectasia. Typical features include the \200\234V \200\235 sign at the base of the neck ante riorly, and the \200\234shawl \200\235 sign at the back of the neck and across the shoulde rs. The heliotrope rash, found in 30 \200\22360% of cases, is a purple/lilac colored suffusion around the eyes, often associated with periorbital edema. It is characteristic but not path ognomic. Some patients have typical cutaneous DM but do not develop overt myositis. The term amyopat hic DM is applied. The same risk of malignancy and systemic complications remains. Calcinosis, cutaneous vasculitis, and ulceration, rare in adults, are more common in juvenile DM. CLINICAL FEATURES OF PM AND DM 401 Malignancy \200 Studies suggest a modest increase in malignancies within 1 \200\2232 year s of onset in DM. The malignancy may predate, predate, or postdate the onset of myositis. I n the majority of cases, cancer and myositis have an independent course. The largest population studies suggest the presence of malignancy to occur in 15% of cases of DM (relative risk in men 2.4, in women 3.4) and 9% of cases of PM (relative risk in men 1.8, and in women1.7). Cancer deaths in studies suggest an increase in DM but not PM, suppo rting a true association with DM, rather than a study bias due to intensive searching. The highest risk appears to be in men older than 45 years with DM who lack myositis autoantibod ies or overlap autoimmune rheumatic disease. Tumors frequent in the general population are frequent in PM and DM. There does, however, appear to be an increase in ovarian, breast, lung, stomach, colon, and bladder cancers out of proportion to that of other tumors. The extent of investigation is controversial. Thorough physical assessment should always in clude rectal, pelvic, and breast examination. Speci \201 c investigations should include a chest radiograph, urinalysis, prostate-speci \201 c antigen in men, fecal occult blood te sting, mammography, and cervical smear, and probably pelvic ultrasound and CA 125 levels in women. Further bowel investigations are open to debate and determined by individual patien t symptoms. Remember that an elevated ALT may be from muscle and may not indicate liver pat hology. Malignancy manifesting as paraneoplastic myopathy and its investigation is discussed in Chapter 4. Systemic manifestations Table 14.3 shows the systemic manifestations of PM and DM. Assessment of disease activity and damage \200 There is a need to be able to accurately a ssess disease activity and damage using valid and reliable instruments, as has been developed in systemic lupus erythe matosus. A disease activity measure might contain the following information: muscle strength measure (e.g., time required to rise from a chair 10 times without using one \200\231s arms) patient and physician global disease activity visual analog scale \200 laboratory tests r esults \200 physical function measures (Health Assessment Questionnaire) \200 patient q uality of life measures (e.g., Short Form-36). A damage score should contain information on damage to different organs. Several activity and damage measures are currently being validated, but no widely-accepted instruments currently exist. CHAPTER 14 Idiopathic in \202 ammatory myopathies 402 Table 14.3 Systemic manifestations of PM and DM Organ/system Features General Fatigue, malaise, weight loss Fevers \200\224in 40% overall Raynaud \200\231s phenomenon Pulmonary Due to muscle weakness: aspiration pneumonia, respiratory failure (low TLC, VC, high RV)* Due to local disease: interstitial \201 brosis (20%), pulmonary vasculitis (rare), pulmon ary hypertension (rare) Due to treatment: hypersensitivity pneumonitis, opportunistic infection Gastrointestinal Esophageal dysphagia \200\224in 30% Striated muscle dysfunction Cricopharyngeal dysfunction Low esophageal dysfunction Stomach and bowel dysmotility \200 Cardiac Cardiomyopathy \200\224<5% Pericardial effusion \200\224up to 20% Heart block \200\224rare Dysrhythmias \200\224uncommon Skeletal Arthropathy Deformity, mild erosive arthritis Renal Very rare. Possible myoglobinuria TLC = total lung capacity; VC = vital capacity; RV = residual volume. \200 Intestinal vas culitis, perforation, and pneumatosis cystoides intestinalis, features of juvenile DM, are very rare in the adult. This page intentionally left blank CHAPTER 14 Idiopathic in \202 ammatory myopathies 404 Investigation of PM and DM The investigation of potential malignancy in DM has been discuss ed earlier in this chapter. Speci \201 c investigations for PM/DM include the following: Muscle enzyme levels \200 Serum levels of enzymes released from damaged muscle may be helpful both in diagnosis and monitoring of the disease; creatine kinase (CK) is most widel y used, although aldolase may be a more sensitive test of muscle turnover. There are a number of causes of a high CK level (see Table 14.4), and levels, particularly in DM, may not be increased despite active myositis and may be in \202 uenced partly by mu scle bulk, i.e., chronic muscle atrophy. The latter is dif \201 cult to assess since measu res of muscle mass do not necessarily correlate well with degree of in \202 ammation. Test s that measure muscle mass are not currently practical for clinical use. Muscle biopsy \200 All patients should have a muscle biopsy to con \201 rm the diagnosis and to exclude conditions that may resemble in \202 ammatory myositis. \200 There is an argument for not doing so in the patient with proximal weakness, elevated enzymes, typical EMG changes, a rash of DM, con \201 rmed myositis-speci \201 c autoantibodies, or an ove rlap autoimmune rheumatic disease and myositis-associated autoantibodies. For most patients , however, it is important to remember that the mimics are more common than the in \202 am matory myopathies themselves. \200 Patients with a clinical diagnosis of PM/DM who do not respond to treatment as expected may bene \201 t from a biopsy in order to con \201 rm a diagnosis. A needle biopsy may be adequate in some cases. However, an open biopsy gives the best picture of muscle architecture and is required for certain functional enzyme studies. \200 Dermatomyositis : perivascular in \202 ammatory in \201 ltrate (B lymphocytes, CD4 T lymphocytes) with capillaritis Polymyositis: intramuscular in \202 ammatory in \201 ltrate (CD8+ T lymphocytes) with muscle \201 ber degeneration and replacement with fat Inclusion body myositis : basophilic intracellular vacuoles ( \200\234inclusion bodies \200\235) Optimal processing and evaluation, minimizing risk of artifact, requires coordination with the pathologist prior to the biopsy taking place. INVESTIGATION OF PM AND DM 405 Table 14.4 The causes of a raised creatine kinase Cause Examples Strenuous prolonged exercise Muscle trauma Diseases affecting muscle Myositis Metabolic Dystrophy Myocardial infarction Rhabdomyolysis Drugs Toxic myopathy Induction of myositis Inhibition of CK excretion (barbiturates, morphine, diazepam) Metabolic abnormalities Hypothyroidism Hypokalemia Ketoacidosis Renal failure Normal variants Ethnic group (often higher normal values in the African-American population) Increased muscle mass Technical artifact CHAPTER 14 Idiopathic in \202 ammatory myopathies 406 Autoantibodies in myositis \200 A high antinuclear antibody (ANA) and myositis-speci \201 c autoantibodies (MSA) favor PM/DM over other myopathies. The various associations with autoa ntibodies are shown in Table 14.5. \200 A modest correlation with anti-Jo-1 antibodies is observed but the usefulness of titers as an index of disease activity is not established. Other MSA have been identi \201 ed, but are not widely available. \200 Antisynthetase an tibodies (such as anti-Jo-1) are associated with interstitial lung disease, arthritis, Rayn aud \200\231s phenomenon, and \200\234mechanic \200\231s hands \200\235 (i.e., dry, cracke d skin across the digits) Anti-SRP antibodies herald an acute-onset, severe illness, often with little evidence of in \202 ammation on biopsy. These patients require aggressive immunosuppression. Electromyography \200 Electromyography (EMG) and nerve conduction studies cannot establish the diagnosis of PM/DM with certainty, but can demonstrate a myopathic process an d help to exclude many other neuropathies and certain myopathies (Table 14.6 gives the diff erential diagnoses of myopathy and Table 14.7 lists drug-induced myopathies in more detail) . 90% of patients will have abnormal EMG studies. \200 Early \201 ndings include low-ampl itude, short-duration, polyphasic potentials, with early recruitment and full interference patterns (i.e., more \201 bers a re required to achieve a given force). The latter features are in contrast to neuropathies where there is decreased recruitment and interference. With time, reinnervation of denervat ed \201 bers leads to high-amplitude, long-duration, polyphasic potentials. Other features include spontaneous activity in up to 75% of cases, \201 brillations, and repetitive discharges akin to myotonia but of constant amplitude th at start and stop abruptly. Imaging \200 Magnetic resonance imaging (MRI), ultrasound, computed tomography, 99 Tc and thallium have been used to assess the distribution of disease. MRI with T2-weighted images and fat suppression or short tau inversion recovery (STIR) is b est at identifying areas of muscle in \202 ammation, atrophy, or fatty in \201 ltration. On MRI, active myositis results in the appearance of muscle edema. When evaluating a patient for weakness, MRI may be particularly useful in distinguishing we akness due to active in \202 ammation from weakness due to previous damage or glucocortico id myopathy (which would not be expected to show muscle edema). Because involvement of muscles may be patchy, MRI may also help identify an optimal site for muscle biopsy. AUTOANTIBODIES IN MYOSITIS 407 Table 14.5 Antibodies in PM/DM Antibody class Antibody subclass Percentage of PM/DM Myositis subgroup Myositis-speci \201 c: In total 30 \200\22340 Anticytoplasmic Anti-Jo-1 20 Antisynthetase syndrome Anti-PL-7/ PL-12/OJ/EJ <3 each Anti-SRP 4 PM Antinuclear Anti-Mi-2 8 DM Anti-56 kDa 90 All Myositis- associated: Anti-PM-Scl 8 PM/ DM \200\223scleroderma overlap Anti-U1- RNP 12 PM/DM overlap syndromes Anti-U2/ U5-RNP <2 PM Anti-Ro and Anti-La 5 \200\22310 Systemic lupus. Sj gren \200\231s syndrome CHAPTER 14 Idiopathic in \202 ammatory myopathies 408 Table 14.6 The differential diagnosis of myopathy Agent Examples Infectious diseases: Viral Retroviruses Picornaviruses Adenoviruses In \202 uenza Hepatitis B and C Bacterial Pyomyositis Lyme myositis Tuberculosis Protozoa Toxoplasmosis Trypanosomiasis Parasites Trichinosis Cysticercosis Fungal Candida Idiopathic: I nclusion body myositis A utoimmune rheumatic disease Other disorders Granulomatous myositis Eosinophilic myositis Focal/orbital myositis Other myopathies: Dystrophies and congenital myopathies Enzyme de \201 ciencies and lipid storage disorders Carcinomatosis Rhabdomyolysis Neurological: motor neuron disease, myasthenia gravis, Guillain \200\223Barr syndrome Endocrine: hypo/hyperthyroidism, cortisol excess Metabolic: hypocalcaemia, hypokalemia Malnutrition Drugs AUTOANTIBODIES IN MYOSITIS 409 Table 14.7 Drug-induced myopathy Clinical picture Examples Drugs implicated in autoimmune myopathy D-penicillamine Cimetidine L-tryptophan Zidovudine Myopathy with weakness, myalgia, and high CK Colchicine Hydroxychloroquine Lipid-lowering agents Cyclosporine Vincristine Carbimazole, propylthiouracil Alcohol NSAIDs \200\224rare in aspirin Rhabdomyolysis picture Alcohol Illicit drugs \200\224cocaine, heroin Amphetamines Barbiturates Statins (particularly high dose) Anesthetics \200\224malignant hyperthermia Psychotropics \200\224neuroleptic- malignant syndrome Other tests \200 The ESR is elevated in 50% of cases but correlates poorly with disease a ctivity and response to therapy. The CRP is not speci \201 c; high levels would suggest a concurrent infection. Complement levels in PM/DM are usually normal. \200 Proteinuria may be the result of myog lobinuria. \200 Serial spirometry for respiratory muscle weakness may be required. CHAPTER 14 Idiopathic in \202 ammatory myopathies 410 Treatment of PM and DM \200 Treatment should be started promptly pending completion of in vestigations, particularly in acute onset weakness, dysphagia, respiratory insuf \201 cien cy, and systemic complications. Corticosteroids form the cornerstone of therapy, and 90% of patients will have at least a partial response. Most patients, however, will also require treatment with a steroid- sparing agent to maintain disease remission and to minimize corticosteroid-exposure. There is a lack of randomized placebo-controlled trials for the treatment of PM and DM. An exercise program helps improve fatigue and muscle strength. Exercise should be used with caution during periods of disease activity, but there is no ev idence that it causes prolonged worsening in muscle enzyme levels or in \202 ammation. Corticosteroids \200 Oral prednisone at 1 mg/kg/day is continued until a decline in CK an d/or a substantial improvement in muscle strength is seen. Severe cases (or extraskeletal i nvolvement) may be treated with IV methylprednisolone 1 g/day for 3 days before starting or al prednisone. High doses may be required for months and a bisphosphonate should be conside red early as prophylaxis against steroid-induced osteoporosis. Adequate calcium and vitamin D intake should always be maintained. Most patients will respond to treatment, but this can be slow and partial. The CK is often seen to change faster than any apparent improvement in strength. Failure to respond may be due to one of several reasons: \200 incorrect diagnosis \200 hereditary myopathy or \200\230inclusion-body \200\231 myositis \200 steroid myopathy \200 permanent loss of s trength \200 unresponsive to steroid therapy. When the initial goals have been reached, the dose of steroid should be tapered gradually over a 6-month period. Immunosuppressive agents \200 Methotrexate (MTX) and azathioprine (AZA) have demonstrable ef \201 cacy in retrospective analysis and, in the case of AZA, a controlled study. \200 MTX 10 \200\22325 mg by mouth or 15 \200\22350 mg subcutaneously per week \200 AZA 2 \200\2233 mg/kg/day AZA may be a better option for patients with interstitial lung disease or hepatitis, but ma y take longer to show effectiveness. Studies have shown a synergistic effect of MTX and AZA where a single drug has failed. The reader is referred to Chapter 5 for discussion on the monitoring of disease-modifying drugs. Cyclosporine is a useful therapy in patients where MTX and AZA have been ineffective or not tolerated. It has been used in combination with MTX or IV gammaglobulin. TREATMENT OF PM AND DM 411 Cyclophosphamide has had variable results and is used in resistant cases or in those cases where there is severe extraskeletal involvement such as vasculitis or lung disease. Tacrolimus has been used in refractory patients with synthetase syndromes, with improvement in muscle strength, lung function, and cutaneous manifestations . It can be given as an ointment. Mycophenolate mofetil (MMF) and chlorambucil are also used. \200 There are several report s of improvements in clinical and laboratory measures in patients with refractory PM/DM aft er receiving in \202 iximab or etanercept. Further work needs to be done in this area. In open label studies, rituximab has been used in refractory DM with clinical improvement. Monoclonal antibodies against complement component C5 (eculizumab) are also being used in t he treatment of DM. Intravenous gammaglobulin (IVIg) \200 IVIg is obtained from healthy donor serum and conta ins a large antibody pool. There is increasing evidence of the ef \201 cacy of this treatment in both PM and DM. High-dose regimens in the form of 2 g/ kg/day for 2 \200\2235 days each month ha ve been advocated. However, the effectiveness of each treatment is of limited duration (6 \200\2238 weeks), tapering and maintenance regimens are empirical and tachyphylaxis may occ ur. It can be used safely in immunocompromised patients and there are no reports of transmi ssion of infectious diseases. Further studies are needed to re \201 ne the place and optim um treatment dose. Treatment of extramuscular disease in PM/DM \200 The rash of DM may respond to the treatm ent of the myositis. If lesions persist, hydroxychloroquine at 200 \200\223400 mg/day or to pical tacrolimus may be of bene \201 t. Photosensitivity can respond to sunscreens. Topica l steroids are often not successful. The treatment of amyopathic DM is controversial. Sunscreens and hydroxychloroquine can be u sed and in some severe cases steroids or immunosuppressives are justi \201 ed for the cuta neous disease. If treatment is withheld due to an absence of myositis, the patient should b e followed closely, especially in the \201 rst 2 years after onset, to avoid delay in tre atment should myositis develop. Calcinosis, principally a problem in juvenile disease, is dif \201 cult to treat.Treatment of the disease may help to prevent calcinosis, but it does not affect estab lished calcinosis. In \202 ammation may respond to colchicine and surgical resection may h elp for accessible deposits. \200 Physical therapy and passive exercises help prevent con tractures, though active exercise is discouraged in the acute period of muscle in \202 ammation. Interstitial lung disease is managed as in other autoimmune rheumatic disease, with oral steroids and oral or IV cyclophosphamide. \200 Distal esophageal dysmo tility does not generally respond to immunosuppression, but measures similar to treatment of re \202 ux may help. CHAPTER 14 Idiopathic in \202 ammatory myopathies 412 Drug-induced myopathy \200 Table 13.7 lists the drugs that commonly cause a myopathy. \200 Recently most attention has been given to HMG-CoA reductase inhibitors (statins) used in lipid-reduction therapy. These drugs are widely prescribed; at orvastatin is the most commonly prescribed drug in the US. In large-scale trials, myalgias have been noted in 11% of patients and signi \201 cant myositis with elevated CK levels in 0.5%. Myalgias and cramp are the most common symptoms reported, and may be exacerbated by the use of other drugs (cyclosporine and \201 brates) or other diseases (hypothyroidism). Patients presenting with muscular symptoms should have their muscle enzyme levels checked and the drug stopped or reduced in dose. Some patients will progress to develop a necrotizi ng myopathy (see below). Prognosis in PM and DM \200 PM and DM are diseases with a high mortality and morbidity. O ne retrospective study estimated a mortality rate of 22%, mostly due to malignancy and pulmona ry disease. The use of prolonged immunosuppressive therapy increases the risk of infection, which may b e with unusual organisms. Case reports have described atypical mycobacterial infections in patients with long- standing PM/DM. A worse prognosis is associated with increasing age, bulbar muscle, and cardiopulmonary involvement. NECROTIZING MYOPATHY 413 Inclusion-body myositis (IBM) \200 This is a distinct disorder that comprises 20 \200\223 30% of idiopathic myositis. It usually begins after the age of 50 years and is three times more common in men. The dif \201 culty in distinguishing it from PM and its insidious onset can lead to considerable d elay in diagnosis. \200 Early in the disease course, there is a signi \201 cant in \202 ammatory component that may partially respond to glucocorticoids. Distal weakness and wasting can be as common as proximal, often involving the lower limbs b efore the upper, and sparing the face. Unlike PM/DM, IBM can present with diminished hand-grip strength, in addition to proximal muscle weakness. Dysphagia is a feature in 40% of cases and myalgias in 20%. \200 An open biopsy (as oppos ed to needle biopsy) is essential to diagnose IBM. A needle biopsy may not be suf \201 cie nt to allow the recognition of important clues that point away from other forms of myositis . \200 Patients do not respond to treatment as well as do those with PM. Immunosuppressio n may lead to reduction in muscle enzyme levels without improvement in strength or function . Treatment usually begins with high-dose corticosteroid for 3 months, adding in MTX or AZA i f there is clinical improvement. If there is continued decline in strength or function, imm unosuppression should be discontinued. Weakness will progress in most patients but this is often very slow. Patients may need assi stance with daily activities within 10 years and some may be wheelchair bound within 15 yea rs of onset of symptoms. Interferon B may be ef \201 cacious for the treatment of inclusion-body myositis. Necrotizing myopathy \200 A rapidly progressive, symmetric, necrotizing myopathy has been described as a paraneoplastic phenomenon. Unlike polymyositis, this form of myopathy is as sociated with prominent muscle necrosis but little or no in \202 ammatory in \201 ltrate. Although the severity of this myopathy does not mirror tumor progression, the cornerstone of therapy is treatment of the underlying malignancy. A second form of necrotizing myopathy has been described in patients with antibodies to HMG -CoA reductase, particularly among patients who have been treated with statins. Unlike poly myositis, patients with this form of myopathy often have minimal weakness. This form of myo pathy is responsive to immunosuppression, but is prone to relapse. CHAPTER 14 Idiopathic in \202 ammatory myopathies 414 PM and DM in children \200 The primary clinical feature of both juvenile DM (JDM) and PM (JPM) is chronic, progressive, proximal muscle weakness. Ful \201 llment of the criteria o f Bohan and Peter is needed to establish the diagnosis (see Table 14.8). In addition to the rash, 3 of the other 4 criteria need to be met for DM. These criteria need to be revised i n children because biopsies and electromyography are now rarely done as they are invasive p ainful procedures. MR is increasingly used to de \201 ne in \202 ammatory changes and to guide biopsies if done. Incidence values for JDM and JPM range form 2.5 \200\2235 per million. \200 The childhood peak for the disease is 5 \200\2239 years of age and JDM is 10 \200\22320 times more common than JPM. Children of African or Asian origin may be at increased risk of chronic myositis. In the United States, Caucasian children with DM are reported more frequently, wi th a male to female ratio of 2:1. In the United Kingdom, Ireland, and China the ratio is in the order of 5:1. \200 JDM is a systemic disease, most commonly affecting the gut, lungs , and nervous system. This is thought to be due to vasculitis that is more marked than in a dult disease. Antinuclear antibodies are seen in 20 \200\22370% of cases of JDM/JPM. Myositis-associated antibodies seen in adult disease (Jo-1) are rarely seen in childhood di sease. The increased frequency of malignancy seen in adults with DM within two years of onset of d isease is not seen in childhood DM or PM. Several agents have been associated with the onset of juvenile DM, which may also explain some temporal, seasonal, and regional differences in disease ons et. The most prominent agents to date have been RNA picornaviruses, group A B -hemolytic st reptococci, and Toxoplasma gondii . The true pathogenesis of juvenile DM in relation to inf ectious agents remains unclear. HLA associations include B8 and DRB1. \200 TNF- A promoter polymorphisms have also been i mplicated in pathogenesis. In general the clinical features of juvenile DM/PM are similar to adult disease. Fever, abd ominal pain, dysphagia, dyspnea and peripheral arthritis are seen. Skin ulceration is seen in 20% of patients and can be severe and disabling. Lipodystrophy is a recognized skin \201 nding. Calcinosis is more common in childhood (10 \200\22330% of patients) and the out come of this ranges from spontaneous resolution to chronic deposition and \202 exion cont ractures. Calcinosis is dif \201 cult to treat and causes long-term morbidity. Rapid disease control is important to help prevent damage. IV or oral corticosteroids are \201 rst line, followed by MTX. JDM in particular bene \201 ts from early and aggressive therapy, which may prevent calcinosis and other complications: \200 Methylprednisolone 30 mg/kg/dose (up to a maximum of 2g) twice weekly for one month \200 Prednisone 2 mg/kg/day \200 Intravenous immunoglobulin 2g/kg administered in divided doses over 5 days PM AND DM IN CHILDREN 415 Table 14.8 Bohan and Peter \200\231s criteria for the diagnosis of juvenile DM/PM Feature DM PM Characteristic rash Yes No Symmetrical proximal muscle weakness in the absence of other rheumatic/endocrine disease Yes Yes Elevated muscle enzymes Yes Yes Muscle histopathology Yes Yes Electromyographic changes of in \202 ammation Yes Yes Other treatments that have been used include IV immunoglobulin and cyclosporine A. Cyclopho sphamide is used for severe multisystem disease. In \202 iximab and IV bisphosphonates have shown some effect on muscle disease and calcinosis. Rituximab and autologous stem cell transplantation have been used in a small number of cases. Early physiotherapy and muscle strengthening is vital, and evidence suggests that this does not affect the in \202 ammatory process. \200 Disease activity a nd damage measures are now being used and validated, as in adult disease. This page intentionally left blank 417 Chapter 15 Primary vasculitides Introduction 418 Large-vessel vasculitis 421 Takayasu \200\231s arteritis 422 Polymyalgia r heumatica and giant cell arteritis 424 Polyarteritis nodosa 429 Granulomatosis with polyang iitis (Wegener \200\231s) 430 Other forms of ANCA-associated vasculitis: microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) 434 Small-ve ssel vasculitis 438 Kawasaki Disease 442 CHAPTER 15 Primary vasculitides 418 Introduction \200 The vasculitides are a heterogeneous group of relatively uncommon diseases that can arise as primary conditions or secondary to an established disease such a s RA (see Chapter 5) or SLE (see Chapter 10). The vasculitides are linked by the presence of vascular in \202 ammation, which can lead to one of two common outcomes: \200 Vessel wall destruction , leading to a neurysm or rupture \200 Stenosis , leading to tissue ischemia and necrosis In 1990, the American College of Rheumatology developed a classi \201 cation system based on vessel size, with the inclusion of a division between p rimary and secondary vasculitis (see Table 15.1). \200 In 1994, the Chapel Hill Consensus Conference (CHCC) developed a standard nomenclature for the primary systemic vasculitides based on clinical and laboratory features, and categorized by vessel size: \200 Large ves sel: Aorta and its major branches ( \200\234great vessels \200\235) \200 Medium vessel: M ain visceral arteries (e.g., renal, mesenteric) \200 Small vessel: Capillaries, arteriole s, and venules In 2012, the second Chapel Hill Consensus Conference recognized two additional categories of vasculitis: \200 Variable vessel vasculitis: Vasculitides th at can affect any caliber blood vessel Single organ vasculitis: Vasculitides that are inherently restricted to a single organ (as opposed to a very limited presentation of a systemic vasculitis). The 2012 Chapel Hill Consensus Conference also adopted a new nomenclature that de-emphasizes the use of eponyms: \200 Granulomatosis with polyangiitis (GPA) for Wegener \200\231s granulomatosis (WG) Eosinophilic granulomatosis with polyangiitis (EGPA) for the Churg- Strauss Syndrome (CSS) ANCA (see below) is helpful to de \201 ne a subset of the small vessel vasculitides that h ave a predilection for the respiratory tract and kidneys. These \200\234ANCA-associated va sculitides \200\235 include granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. This classi \201 cation system is not perfect: Patients with \200\234large vessel vasculitis \200\235 and \200\234small vessel vasculiti s \200\235 can have disease that affects some medium-sized vessels. Not all patients with \200\234ANCA-associated vasculitis \200\235 have detectable levels of ANCA. This is still a useful framework for the clinician, however, since categorizing the patient into one of these groups can narrow the differential diagnosis con siderably. INTRODUCTION 419 Antineutrophil cytoplasmic antibody (ANCA) \200 ANCA exist in 2 main forms: Cytoplasmic (C-ANCA): caused by antibodies against proteinase-3 (PR3-ANCA), and is generall y associated with granulomatosis with polyangiitis (Wegener \200\231s granulomatosis) Perinuclear (P-ANCA): caused by antibodies against myeloperoxidase (MPO-ANCA), and is generally associated with microscopic polyangiitis and e osinophilic granulomatosis with polyangiitis (the Churg-Strauss Syndrome) Other ANCA-staining patterns (i.e., noncytoplasmic, nonperinuclear) can occur; moreover, the P-ANCA pattern may be caused by antibodies against antigens other than myeloperoxidase. These are sometimes referred to as \200\234atypical ANCA, \200\235 a nd do not predict the presence of vasculitis, although they can be found in Crohn \200\231s disease, immune-mediated neutropenia, and other autoimmune diseases. \200 Counterintuiti vely, patients with \200\234ANCA-associated vasculitis \200\235 can be ANCA-negative in up to 50% of cases. Therefore, the absence of ANCA does not completely exclude the diagnosis of an ANCA- associated vasculitis. Patients with active, untreated disease, however, are more likely to be ANCA-positive. The exact role that ANCA may play in the pathogenesis of vasculitis is still incompletely undersotood. Disease and damage assessment \200 To be complete, any description of a chronic disease ( such as primary systemic vasculitis) must include both a description of disease activity an d a description of disease damage. The concept of damage denotes the aspects of disease that are unlikely to reverse with immu nosuppression (such as pulmonary \201 brosis or renal insuf \201 ciency). Clinical trials of vasculitis commonly use the Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI) to assess activity and damage, respectively. These instruments are most helpful for the assessment of the small- and medium-vessel vasculitides. Other clinical indices exist. The French Vasculitis Study Group (FVSG)