Authors

M. de Visser, M.D., Ph.D., Professor of Neuromuscular Diseases
J.E. Hoogendijk, M.D., Ph.D.
J. van de Vlekkert, M.D.

Clinical features
Patients with PM or DM present with subacute (weeks to months) progressive, symmetrical, proximal muscle weakness of arms and legs, and neck flexor weakness. They often complaint about pain and tenderness in the affected muscles. Dysphagia, caused by both pharyngeal weakness and hypomotility of the lower oesophagus, has been reported in one third of patients. General symptoms like fatigue, weight loss, fever and arthralgias are often present. In severe cases of both types of myositis, respiratory muscles can be involved (up to 10%). Interstitial lung disease is often seen in patients with autoantibodies to tRNA synthetases or a mucinlike glycoprotein: anti-synthetase syndrome. Cardiac disturbances include atrioventricular conduction defects, tachyarrhythmias, myocarditis, dilated cardiomyopathy and heart failure. The clinical relevance of the cardiac findings is probably neglectable.

The typical skin rash in dermatomyositis includes the following features:

• Gottron’s sign (symmetrical erythematous plaques or bluish atrophic maculae with or without edema over the elbows, knees and medial malleoli);
• Gottron’s papules (symmetrical bluish non-scaly papules over the dorsal interphalangeal and/or metacarpophalangeal joints, elbows, knees or medial malleoli);
• Heliotrope erythema (red-violaceous discolouration of the upper eyelids or the peri-orbital tissue with or without edema);
• Erythema over the dorsal side of hands, fingers, upper legs and arms, shoulders and neck (shawl sign), upper chest (V-sign) and forehead;

Poikiloderma atrophicans vasculare (erythema, teleangiectasia, hypo- and hyperpigmentation and atrophy of the skin of the shoulders, lumbar back region and upper chest. The other  skin abnormalities, like dilated capillary loops at the base of the fingernails with thickened and distorted cuticles (nailfold lesions), cracked skin of the  fingers and palms with ‘dirty’ horizontal lines (mechanics hands)’, Raynaud phenomenon, etcetera, are less characteristic. The skin manifestations often precede the muscle weakness or can be present without muscle weakness (dermatomyositis sine myositis or amyopathic dermatomyositis). Subcutaneous calcification is often present in childhood dermatomyositis, but are seldom seen in adults. Inclusion body myositis progresses very slowly over many years with a painless, asymmetrical proximal as well as distal weakness. Early involvement with weakness and muscle wasting of the wrist and finger flexors, quadriceps femoris and ankle dorsiflexors is often present. Later, dysphagia occurs in almost half of the patients, sometimes necessitating a cricopharyngeal myotomy. Mild facial weakness can be present. The extraocular muscles are never affected.

Natural course and prognosis
The natural course of polymyositis and dermatomyositis has never been evaluated, but spontaneous remission has been described. It is difficult to analyse the outcomes of patients after treatment, because studies often use various outcome measures, many studies use inadequate treatment and inclusion body myositis (unresponsive to treatment) is often not sufficiently excluded. After treatment, about 25% is markedly disabled or dead and 30% is in a remission. 5-year survival is about 95% and the 10-year survival about 84%.

Epidemiology

The exact frequencies of dermatomyositis and polymyositis are unknown, because most studies used the Bohan and Peter criteria which can not differentiate PM from IBM. The incidence (in the total population of children and adults) of IIM without distinguishing between DM, PM or sIBM is 5.5 (95% CI 4.7-6.4) to 7.7 (95% CI 6.0-9.0) per million person years). These figures are derived from retrospective North-American and Anglo-Saxon studies. Extrapolation to the Dutch situation would yield approximately 100 incident cases per year. In North-America and the United Kingdom, the incidence of juvenile DM varies from 1.5 to 4 per million children per year.
A study on the prevalence of IBM in the Netherlands showed 4.9 patients per million inhabitants, but this is probably an underestimation.
Juvenile DM is two times more prevalent in girls than in boys. Th mean age of onset is 6.8-7.4 years. In particular middle-aged men develop sIBM. The male-female ratio in sIBM is 2:1. The mean age of onset ranges is 56.1-64.3 year (range 28-85).

Differential diagnosis

Muscle weakness with a subacute onset of limb-girdle muscle weakness can have many causes like electrolyte disturbances (hypokalemia, hypercalcemia), metabolic diseases (periodic paralyses), enzyme deficiencies (carnitine-palmitoyl transferase deficiency), other immune-mediated  diseases (myasthenia gravis, Guillain-Barré Syndrome), endocrine diseases (hyperthyroidism, hypothyroidism, hyperparathyroidism, Cushing syndrome, Addison’s disease),  drugs, toxins (ethanol, corticosteroids, colchicine, D-penicillamine, lipid-lowering drugs, zidovudine) and infections (influenza, toxoplasmosis, human immunodeficiency virus).

Even muscular dystrophies can have a seemingly subacute onset although careful history taking usually shows that signs and symptoms have started much earlier.

Ancillary investigations

The diagnosis of myositis is based upon the history, clinical examination, assessment of serum creatine (CK) activity and skin or muscle biopsy findings.In patients with characteristic skin lesions (Gottron’s sign or papules and heliotrope edema) no additional investigation has to be performed since these features are pathognomonic for dermatomyositis. If less charcteristic skin abnormalities are found or if the dermatologist is in doubt about the presence of Gottron’s sign or papules and heliotrope edema a biopsy of affected skin can be performed.

In all other cases of subacute myositis, a muscle biopsy should be taken from an affected (weak) muscle. A MRI scan of the muscles can help to guide the biopsy site, since the inflammation can be patchy. Inflammation in the muscle will yield a high intensity signal on the T2-weighted STIR (fat-suppression) images. A biopsy including the fascia  is preferred if the inflammation seems to be restricted to the fascia, as may been often in myositis associated with a connective tissue disorder. In patients suspected of sporadic inclusion body myositis muscle imaging (CT or MRI) preceding the muscle biopsy can be useful in order to avoid ending up with a specimen that shows end-stage disease and does not allow interpretation.

In polymyositis, cytotoxic (CD8-positive) T lymphocytes and macrophages are present at the level of the endomysium, i.e., between muscle fibres. They surround and invade healthy muscle fibres expressing MHC class I antigens, leading to muscle cell degeneration and necrosis. Other, non-specific abnormalities are necrotic and regenerating muscle fibres. These muscle biopsy findings are only rarely encountered, rendering PM defined by the above histopathology features extremely rare. However, if one defines this disorder on clinical grounds (subacute symmetrical muscle weakness with a limb-girdle distribution without skin changes), the cellular infiltrates are usually found at perivascular and/or perimysial sites.

In sporadic inclusion body myositis endomysial cell infiltrates mainly consisting of CD8-positive lymphocytes are found as well, but in addition vacuolated muscle fibres with basophilic granular deposits around the edges (rimmed vacuoles) are found within the muscle fibres. Sometimes intracellular amyloid deposits can be seen. Other abnormalities which do not contribute to the diagnosis include atrophic and necrotic muscle fibres and ‘ragged red fibres’. By electron microscopy, abnormal tubular filaments can be found in the nuclei or cytoplasm, but this investigation is not necessary for the diagnosis.

In dermatomyositis, the inflammation with CD4-positive B lymphocytes, T-helper cells and macrophages is found at perivascular sites or in the interfascicular septae (perimysium). Microinfarcts of the muscle fascicles, predominantly at the periphery of the fascicles and subsequent regeneration of the muscle fibres result in the characteristic perifascicular atrophy. There is also a reduction in the number of capillaries. Other non-specific abnormalities include necrotic and regenerating muscle fibres and an increase in connective tissue. The perivascular CD4-positive cells are also found in the skin. At the ultrastructural level, endothelial swelling and microtubular inclusions in the capillaries can be found in early stages of DM.

In myositis associated with a connective tissue disorder, the inflammation is often present in the fascia and in the interfascicular septae around blood vessels.

In dermatomyositis and polymyositis, serum CK activity is usually markedly elevated, but can be normal in DM. In inclusion body myositis, serum CK activity is normal or only moderately elevated.

In all types of myositis, electromyography (EMG) will show myopathic findings (myopathic motor unit action potentials) and spontaneous muscle fibre activity ( fibrillation and positive sharp waves), which do not differentiate between the different types of myositis. EMG is not used for the diagnosis of IIM, but is useful to differentiate between a relapse of myositis and corticosteroid myopathy.

Antibodies against nuclear or cytoplasmic antigens, ribonucleoproteins involved in protein synthesis (anti-synthetase) or translational transport (anti-signal-recognition particle), are found in about 20% of patients with polymyositis and dermatomyositis, but are rarely present in inclusion body myositis. Anti-Jo-1, the antibody against histidyl-tRNA synthetase, accounts for 80% of all the anti-synthetases and seems to be associated with a syndrome with myositis, arthritis, Raynaud’s phenomenon and interstitial lung disease which may bear a less favourable prognosis. The clinical use of other myositis specific antibodies remains unclear. A careful history and examination aimed at detecting a malignancy followed by a spiral CT scan of the chest and mammography in females have to be performed in patients with DM. Imaging of the pelvic region including the ovaries and the gastro-intestinal tract are only carried out upon indication. The history and examination should be repeated annually. In Asian patients the search should be aimed at detection of nasopharyngeal cancer. Adult dermatomyositis has an increased risk of developing a malignancy (standardised incidence ratio 4.3 [95% CI 2.3-8.1]).  The malignancies include cancers of the lung, breast, ovaries, gastrointestinal tract and non-Hodgkin lymphomas. Nasopharyngeal cancer is especially common in Asian patients. Most malignancies are found within the first three years after the presentation of the myositis, but even up to 5 years the risk of a malignancy is increased. Cancer can also precede DM. The studies on associations between cancer and PM were based on the Bohan and Peter diagnostic criteria which hampers interpretation of the data. An association between juvenile DM and malignancies has never been demonstrated. Dermatomyositis and polymyositis are seen in association with various connective tissue diseases  such as systemic sclerosis, scleroderma, mixed connective tissue disease, rheumatoid arthritis, lupus erythematosus, and Sjögren’s syndrome. Inclusion body myositis has been described in patients with lupus erythematosus, systemic sclerosis, Sjögren’s syndrome, sarcoidosis and thrombocytopenia.

Genetics

Genetic factors may have a role in polymyositis and dermatomyositis, as suggested by rare familial occurrences and association with certain HLA genes.

In addition to sporadic IBM, a hereditary form has been described. These patients present very little muscle inflammation, although other pathological changes are similar to those observed in sporadic inclusion body myositis.

Therapy

Dermatomyositis and polymyositis are considered to be responsive to immunosuppressive and immunomodulating therapies, in contrast to IBM, which is refractory to all treatment.

In polymyositis and (juvenile and adult) dermatomyositis, first line treatment with prednisone (1-1.5 mg/kg/day) has been generally accepted, although randomised placebo-controlled trials have never been performed.

Retrospective studies have shown that prednisone reduces morbidity and improves muscle strength and function. The response to steroid therapy varies greatly from patient to patient and conclusions on steroid efficacy differ from one series to the next. Between 58 and 100% of DM patients have at least a partial response; 30-66% returns to normal strength with prednisone. For polymyositis over 80% improve; 10-33% returns to normal. After 3-6 weeks of high dose prednisone follows a slowly tapering off in more than one year. When no response is noted after an adequate trial of high-dose prednisone, other alternative diagnoses (like IBM) should be considered. In patients with DM intravenous immunoglobulin can have a short-lasting beneficial effect. The affected skin has to be protected against the sun. Treatment with hydroxychloroquin should be given in amyopathic DM.

When treatment with adequate dose of prednisone during at least 4-6 weeks fails, judged on insufficient improvement of muscle strength, frequent relapses during tapering off the dose occur, or unacceptable side effects are present, a second line therapy is started. Many different treatments are being used for the second line treatments in PM and DM, and there is no consensus which drug is best. Only one study demonstrated short-term efficacy of treatment with intravenous immunoglobulin in dermatomyositis. Other second-line treatments include methotrexate, azathioprine, cyclophosphamide, and cyclosporine. Treatment effects should be monitored by assessing functional measurements and muscle strength assessments in combination with estimation of serum creatine kinase activity (sCK). Serum CK activity can be elevated in patients with no objective weakness or sCK can be normal or only mildly elevated in patients with active disease, and therefore assessment of sCK as the only monitoring parameter does not suffice. An increasing sCK can be a warning of a relapse, but without objective clinical detoriation, adjustment of the treatment should not be made. When patients become weaker during long-term corticosteroid treatment, a steroid myopathy should be considered in which a type 2 muscle fibre atrophy results in muscle weakness. This must be differentiated from a relapse with electromyography, sCK estimation (normal) or a second muscle biopsy. Osteoporosis prevention:Patients who are expected to be treated with 15 mg or more prednisolone equivalent per day for more than 3 months and postmenopausal women and older men (70 years or older) who will be treated with 7.5 mg or more prednisolone equivalent per day should be started on a bisphosphonate (Fosamax 10 mg daily or 70 mg once a week) as soon as possible. Other patients who will be treated with 7.5 mg or more prednisolone equivalent per day should take a bisphosphonate if their Z-score is below -1 or their T-score is below -2.5. Persons with less than 1000-1200 mg calcium in their daily food who are using corticosteroids, persons with osteoporotic fractures and persons who are being treated with drugs for osteoporosis are eligible for calcium supplementation.

Links

CBO website