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Myositis

Essentials

Rare inflammatory autoimmune diseases
Systemic diseases where other organs (skin, joints, lungs, the gastrointestinal tract and the heart) may also be affected, and there may be systemic symptoms (fever, weight loss and fatigue)
Diagnostic investigations and planning of treatment should be concentrated in units with appropriate experience.
Patients with severe symptoms should be referred to hospital as emergency cases (severe general symptoms, dyspnoea or serious swallowing problems, for example).
Inclusion body myositis is the most common degenerative muscle disease in the elderly with no course-altering medication available.
All patients benefit from regular training to maintain muscle fitness and strength.

Epidemiology

According to a Swedish register study, the annual incidence of myositis is 11/1 000 000 and its prevalence is 14/100 000 4.
The disease is slightly more common in women than in men (ratio 1.3/1)
It occurs in adults, usually after the age of 45 years.
Childhood dermatomyositis is rare.

Symptoms

Usually subacute weakness of upper and lower limb muscles, predominantly in the proximal parts
- Causes difficulty in, for example, walking up and down stairs, getting up from a squatting position, lifting things to upper shelves.
There may be muscle pain and tenderness but pain is not usually the predominant symptom.
Dermatomyositis causes skin symptoms (see in more detail below here; pictures F1 F2)
Systemic symptoms, such as slight fever, fatigue and weight loss may occur.
Some patients have respiratory symptoms (cough or dyspnoea). These may be due to associated interstitial parenchymal lung disease, which may be the first sign of the disease.
Some patients may have dysphagia with possible risk of aspiration or asphyxiation.
In addition to the skin and lungs, the disease may also affect joints, the heart or the gastrointestinal tract.
- Joint symptoms include pain and nonerosive arthritis.
- Cardiac symptoms are rare but patients may have conduction disorders or develop cardiac failure.
- In addition to dysphagia, there may be reflux oesophagitis, diarrhoea, constipation and abdominal pain.

Workup and diagnosis

In primary health care: CK, basic blood count with platelet count, ESR, CRP, TSH, creatinine and anti-nuclear antibodies.
- The basic blood count with platelet count is usually normal, CRP normal or slightly elevated, and ESR may be either normal or elevated.
- In the active and acute stages of myositis, CK levels are usually in the order of thousands but, at a calm stage, they may even be normal.
  - Slightly or somewhat increased CK levels are common incidental findings.
  - CK levels often increase in association with physical exertion (check again after a period of rest), and the levels should be interpreted considering the patient's size and muscle bulk.
  - Hypothyroidism (TSH) and medication (such as statins) may raise CK levels.
ENMG can be performed in primary health care if readily available.

Diagnosis in specialized care

In addition to the clinical picture and elevated CK levels, muscle MRI and ENMG are used for diagnosis.
MRI is used to assess the extent, muscle distribution and activity of myositis and to guide muscle biopsy.
Biopsy of an affected muscle forms the cornerstone of diagnosis.
Myositis-specific and myositis associated autoantibodies are used to classify diagnosed myositis or interstitial parenchymal lung disease, to choose the treatment and to assess the prognosis.
- Fewer than 2 in 3 patients with active myositis have antibodies.
- Antibodies cannot be used for screening in patients with vague symptoms because in unselected material, many false positive results are obtained.
Further investigations (such as heart and lung imaging and function tests and, possibly, screening for cancers 1) are planned individually depending on the clinical picture, myositis subtype and treatment response.
Division of labour
- Rheumatologist: classic symptoms of myositis (see section on Symptoms here) or suspicion of myositis involving rash, arthritis or symptoms or findings suggesting a generalized connective tissue disorder
- Neurologist: suspected inclusion body myositis (IBM) or, if muscle weakness has developed slowly, there is muscular atrophy and no signs or findings suggesting connective tissue disorder

Classification

Myositis is traditionally classified as either polymyositis, dermatomyositis or inclusion body myositis. Today, due to improved understanding of the pathophysiology and to the finding of myositis antibodies, there are several clinical subclasses.
The clinical picture, myositis antibodies, muscle biopsy findings and treatment response help in classification.
As clinical pictures are heterogeneous, some cases can be classified as belonging to several subclasses simultaneously.
Dermatomyositis (DM, skin symptoms; Images F1F2)
- Purplish erythema and oedema of the eyelids and around the eyes (heliotrope rash)
- Rash on the chest, upper back ("shawl pattern")
- Gottron's papules on the knuckles (erythematous purplish lesions on the extensor surfaces of metacarpophalangeal and proximal interphalangeal joints; Image F2)
- Purplish rash on the elbows, knees, ankles (Gottron's signs)
- Rash on sun-exposed areas
- In rare cases there is calcification and ulceration of the skin.
- Dilated pathological nailfold capillaries can be seen in videocapillaroscopy (picture article Videocapillaroscopy).
- In most cases, muscle biopsy shows perivascular inflammatory changes and capillary damage at the margins of muscle fibres.
Amyopathic dermatomyositis
- Typical skin symptoms without active myositis
- This form of disease may be associated with interstitial parenchymal lung disease (anti-MDA5 antibody positivity, for example, is associated with severe parenchymal lung disease).
Cancer-associated myositis (CAM)
- About 10-15% of cases of dermatomyositis in adults are paraneoplastic.
- Particularly in association with breast, ovarian, lung and prostate cancers
- There is association with cancer in 40-80% of anti-TIF-gamma antibody positive adults.
Juvenile dermatomyositis (JDM)
- The most common form of myositis in children
Antisynthetase syndrome (ASS)
- Messenger RNA synthetase antibodies, such as anti-Jo-1 and anti-PL-7
- In addition, the patient may have interstitial parenchymal lung disease, arthritis, Raynaud's syndrome Raynaud's Phenomenon (RP) or White Finger Disease and “mechanic's hands”, i.e. dry, cracking fingertips.
Overlap myositis
- Associated with other rheumatological diseases, such as SLE , Sj�gren's syndrome Primary Sj�gren's Syndrome, systemic sclerosis Systemic Sclerosis or rheumatoid arthritis Rheumatoid Arthritis or the patient may have autoantibodies associated with such diseases.
Necrotizing autoimmune myopathy (NAM)
- Often acute; CK levels may be significantly elevated, as high as tens of thousands.
  - A more chronic clinical picture is also known, where CK levels are usually more moderate, no higher than a few thousands.
- May be triggered by medication (statins) or a viral infection or sometimes associated with cancer.
- Anti-SRP (signal recognition particle), anti-HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) antibodies
- Anti-HMGCR antibody positive NAM is most often triggered by a statin.
  - In contrast with toxic statin myopathy, the myositis will not subside even if the statin is withdrawn but requires immunosuppressive treatment.
  - It may occur only after several years of using statins.
- Muscle biopsy will show necrotic muscle fibres, some inflammatory cells, complement-positive capillaries
Inclusion body myositis (IBM)
- The most common type of myositis in patients over 45 years
- The typical clinical picture consists of asymmetric, progressive weakness and atrophy of quadriceps muscles in legs and deep finger flexors in arms (weak flexion of proximal interphalangeal [PIP] joints).
- More than half of the patients have swallowing problems at some stage of the disease.
- There may be slight weakness of respiratory and facial muscles.
- CK is usually slightly elevated or normal.
- Main findings in muscle biopsy: inflammatory cells around muscle fibres, myodegeneration and protein accumulation (peripheral vacuoles), as well as mitochondrial pathology
- The treatment is symptomatic.
- Differential diagnosis versus inflammatory myopathies can be done based on the clinical picture and muscle biopsy.
- See also http://www.orpha.net/en/disease/detail/611.
Polymyositis (PM)
- Today, myositis is classified as polymyositis if it is not consistent with any other subclass.
- Inflammatory cells are concentrated around muscle fibres.
- See also http://www.orpha.net/en/disease/detail/732.
In addition, there are very rare subclasses,
- such as muscular sarcoidosis and eosinophilic, granulomatous, focal, nodular, and orbital myositis.

Myositis-specific and myositis-associated autoantibodies.

Autoantibody	Clinical picture	Further information
Jo-1, PL-7, PL-12, EJ, OJ, KS, Zo, Ha	Antisynthetase syndrome: Raynaud, ILD, arthritis, mechanic's hands, fever, DM rashes common	Jo-1 about 25%, the rest 1-5%. Cytoplasmic RNA-synthetase molecule antibody
Mi-2	Classic DM, rash and muscle weakness	About 10%, good response to glucocorticoid treatment. Rarely ILD or cancer
SAE1	Classic cutaneous DM, muscle weakness beginning with dysphagia	Rare, lungs affected in a Japanese cohort
MDA5	Amyopathic DM, rapidly progressive ILD, skin ulceration, panniculitis	Refractory, requires early active treatment. More common in people of Asian descent
NXP2	Classic DM skin, possibly severe muscle symptoms in the beginning	Juvenile DM with associated calcinosis. May be associated with cancer in adults.
TIF1-γ	Classic, rather severe cutaneous DM with sun sensitivity, muscle symptoms may be mild	About 25% juvenile DM. In adults (over 40 years), strong association with cancer (in as many as 40-80%)
SRP	Necrotizing autoimmune myopathy, dysphagia	Cytoplasmic signal recognition particle antibodies
HMGCR	Immune-mediated necrotizing myopathy	Cytoplasmic 3-hydroxy-3-methylglutaryl-CoA-reductase antibodies. About 2 in 3 use statins
Anti-cN-1A	About 33% have inclusion body myositis	Cytoplasmic antibody, Sj�gren and SLE in 30%, in DM and polymyositis, in 0-5%
RO52(SSA), Ku72/86, PM-Scl100, PM-Scl75, Anti-U1RNP	Overlap myositis	Associated with or showing features of Sj�gren's syndrome, systemic sclerosis, mixed connective tissue disease

In the antinuclear antibody test (ANA), the staining pattern of the nucleus or the cytoplasm may suggest myositis autoantibodies. As it is too insensitive for detecting myositis autoantibodies, however, it is not suitable for screening.
ILD = interstitial lung disease, DM = dermatomyositis
Modified from textbook article: Mali M, Jokela M. [Diagnostic investigation of myositis], table 1. In: Kauppi M, Karjalainen A, Pirilä L, et al. (eds.). [Rheumatic diseases] [online]. Duodecim Publishing Company Ltd, 2023.

Differential diagnosis

Myositis is rare, and any differential diagnosis may be extensive (with just some of the possibilities mentioned below). Medication may be associated with severe adverse events. Therefore, diagnostic investigations and planning of treatment should be concentrated in specialized centres with appropriate experience.
Rhabdomyolysis Rhabdomyolysis
Infectious myositis (influenza A and B Influenza, HIV HIV Infection, dengue Viral Diseases in Warm Climates, toxoplasmosis Toxoplasmosis, tuberculosis Diagnosing Tuberculosis)
Vasculitis Vasculitides
Hereditary muscle diseases Hereditary Myopathies
ALS Amyotrophic Lateral Sclerosis (ALS), CIDP http://www.orpha.net/en/disease/detail/2932, Guillain-Barré syndrome (polyradiculitis) Guillain-Barré Syndrome (Polyradiculitis)
Myasthenia gravis Myasthenia Gravis
Polymyalgia rheumatica Polymyalgia Rheumatica
Hypothyroidism Hypothyroidism
Fibromyalgia Fibromyalgia
Musculoskeletal diseases
Sarcopenia associated with normal ageing (see Nutritional disorders in the elderly Nutritional Disorders in the Elderly)
Adverse effects pharmaceuticals and intoxicants
- Statins
- Larger doses of glucocorticoids for longer periods may be associated with myopathy and muscle weakness without increased CK levels.
- Very rarely drugs such as colchicine, certain antipsychotics and antidepressants, hydroxychloroquine, certain HIV drugs and antifungals
- Any drug interactions should be kept in mind. Check locally available database(s).
- Alcohol, cocaine, heroin and other intoxicants

Treatment Intravenous Immunoglobulin for Dermatomyositis, Treatment of Dysphagia in Long-Term, Chronic Muscle Disease, Diagnosis of Pneumonia by History and Physical Examination

Treatment strategy, prognosis and further follow-up depend on the diagnosis.
All people benefit from regular training maintaining muscle fitness and strength.
- Individual rehabilitation plans should be made in multidisciplinary cooperation (physician, physiotherapist, rehabilitation advisor).
IBM is a chronically progressive disease. Its treatment consists of rehabilitative care, and there is currently no medication available influencing the course of the disease.
Beginning treatment
- First-line treatment: a glucocorticoid, such as 1 mg/kg prednisolone for 4-6 weeks, tapered off slowly
- For progressive symptoms: 1 g i.v. methyl prednisolone daily for 3-5 days
- Maintenance treatment +/- glucocorticoid: azathioprine (no more than 3 mg/kg/day) or methotrexate (20 mg once a week) or mycophenolate (2 000-3 000 mg/day) or ciclosporin (no more than 300 mg/day)
- Particularly for patients with DM not responding to glucocorticoid therapy: 2 g/kg i.v. immunoglobulin Intravenous Immunoglobulin for Dermatomyositis for 2-5 days every 4-8 weeks
- Other treatment, as necessary: rituximab, for example
Remember ulcer and osteoporosis prophylaxis, as necessary; see articles on Pharmacological glucocorticoid treatment Pharmacological Glucocorticoid Treatment and Osteoporosis Osteoporosis.
Patients with dermatomyositis should avoid sunshine (protective clothing, high sun protection factor in sun protection products).
For skin symptoms, a topical glucocorticoid or calcineurin inhibitor, as well as hydroxychloroquine 300 mg/day orally, may be used, as necessary.

Follow-up and prognosis

If the response to treatment is poor, it should be reassessed whether the diagnosis is correct or whether there are signs of paraneoplasia.
Response to treatment is monitored based on the following:
- Patient's condition (general assessment of disease activity by the patient and the doctor)
- Functional ability (e.g., the Health Assessment Questionnaire, HAQ, see locally available version)
- Muscle strength testing
- CK levels
- Muscle MRI, as necessary.
If the CK level is elevated, elevated levels of aminotransferases (AST , ALT), LD and TnT in the absence of liver or heart damage are often also seen.
Myositis is associated with about 10% excess mortality compared to the general population. The additional mortality is associated with pulmonary complications and associated cancers.
According to a study performed in the beginning of the 21st century, at 5 years, 20% of patients were in remission without medication, 20% had polycyclic clinical disease and in the rest the cases could be described as chronic 7.
Today, the prognosis of the disease can perhaps be improved due to more active treatment and more accurate diagnosis.
Long-term follow-up in specialized care is necessary, at least if the disease is even slightly active.
If the disease remains calm for a long time without demanding immunosuppressive medication, it can be followed up in primary health care.
- - The patient's general and muscle condition should be monitored.
  - CK should be tested, as necessary.
  - Depending on medication, other laboratory tests should be done; see
    - Rheumatoid arthritis > Safety monitoring tests Rheumatoid Arthritis
    - See also local recommendations concerning relevant safety monitoring tests.
  - If reactivated myositis is suggested, specialized care should be consulted.

References

Oldroyd AGS, Callen JP, Chinoy H, et al. International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening: an International Myositis Assessment and Clinical Studies Group (IMACS) initiative. Nat Rev Rheumatol 2023;19(12):805-817 [PubMed]
Oldroyd AGS, Lilleker JB, Amin T, et al. British Society for Rheumatology guideline on management of paediatric, adolescent and adult patients with idiopathic inflammatory myopathy. Rheumatology (Oxford) 2022;61(5):1760-1768 [PubMed]
McLeish E, Slater N, Sooda A, et al. Inclusion body myositis: The interplay between ageing, muscle degeneration and autoimmunity. Best Pract Res Clin Rheumatol 2022;36(2):101761 [PubMed]
Svensson J, Arkema EV, Lundberg IE, et al. Incidence and prevalence of idiopathic inflammatory myopathies in Sweden: a nationwide population-based study. Rheumatology (Oxford) 2017;56(5):802-810 [PubMed]
Dalakas MC. Inflammatory muscle diseases. N Engl J Med 2015;372(18):1734-47. [PubMed]
Dobloug GC, Antal EA, Sveberg L, et al. High prevalence of inclusion body myositis in Norway; a population-based clinical epidemiology study. Eur J Neurol 2015;22(4):672-e41 [PubMed]
Bronner IM, van der Meulen MF, de Visser M, et al. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis 2006;65(11):1456-61 [PubMed]

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