Polymyositis

                                 Dr. KS Dhillon

Introduction

There are four major subtypes of idiopathic inflammatory myopathies. These include dermatomyositis, polymyositis, inclusion body myositis, and necrotizing myopathy. Bohan and Peter [1] categorized myopathies into seven classes. Polymyositis is an autoimmune and chronic inflammatory myopathy. It is characterized by symmetrical proximal muscle weakness due to the involvement of endomysial layers of skeletal muscles. Dermatomyositis, on the other hand, involves the perimysial layers of muscles along with dermatological involvement [2]. 

Polymyositis develops over the months. Inclusion body myositis (IBM), on the other hand, is a slowly progressive chronic myopathy that develops in older individuals over a period of months to years and the symptoms are more severe. Inclusion body myositis develops secondary to either an autoimmune reaction or due to a degenerative process that results from persistent retroviral infection such as human T-cell leukemia virus type 1 (HTLV-1) [3]. Since polymyositis is an autoimmune rheumatological disorder, it requires long-term treatment with steroids or immunomodulators. At the same time treatment of the underlying etiological factors is carried out. 

Etiology

Polymyositis is an autoimmune disorder. It develops due to abnormal activation of cytotoxic T lymphocytes (CD8 cells) and macrophages against muscular antigens. There is strong extrafusal muscular expression of major histocompatibility complex 1 causing damage to the endomysium of skeletal muscles [4,5].

Rhabdomyolysis is produced by different cytokines, including interleukins, and tumor necrosis factor. It occurs in individuals who are already suffering from some kind of systematic disease due to viral infections, malignancies, or other autoimmune disorders. 

The viruses that commonly cause polymyositis are the retroviruses human immunodeficiency virus (HIV) and HTLV1, and hepatitis C virus. They cause inflammatory muscle degeneration by causing endomysial damage leading to edematous swelling and nodular mass formation in the myocytes [6,7].

Coxsackie B virus can also produce polymyositis. This autoimmune disorder is due to the abnormal functioning of the major histocompatibility complex secondary to the release of cytokines that damage the intima and endothelium of blood vessels [8].

Malignancies such as lung carcinoma, genitourinary malignancy or lymphomas, etc can also cause polymyositis-induced rhabdomyolysis. The presence of polymyositis also increases the possibility of developing carcinoma in 2-5 years after the diagnosis, especially non-Hodgkin lymphoma. Lung carcinoma and bladder carcinomas can often develop [9].

Other causes of polymyositis include:

• The presence of certain HLA variants (A1, B8, DR3)

• The presence of another autoimmune disease such as celiac disease [10]

• The use of few medications such as hydralazine, procainamide, antiepileptics, and angiotensin-converting enzyme (ACE) inhibitors due to their ability to act as a hapten. There was a study that reported that 24% of patients on statin therapy developed polymyositis [11].

Bohan and Peter classified the idiopathic inflammatory myopathies as follows [12]:

I - Primary idiopathic polymyositis

II - Primary idiopathic dermatomyositis

III - Polymyositis or dermatomyositis associated with malignancy [13]

IV - Childhood polymyositis or dermatomyositis

V - Polymyositis or dermatomyositis associated with another connective tissue disease

VI - Miscellaneous eg, eosinophilic myositis, myositis ossificans, focal myositis, giant cell myositis

Epidemiology

Among the middle-aged population in the United States, autoimmune disorders are the leading cause of increased mortality. The incidence rates vary [14]. Polymyositis usually affects people above the age of 20 years and is rarely present in childhood. Dermatomyositis has a bimodal age distribution affecting the population between 5 to 15 years and 45 to 60 years [15]. 

The incidence of polymyositis is double in women as compared to men.

In the USA, the rate of development of polymyositis is about 0.5 to 8.4 cases per 100,000 individuals. It is more common in Blacks than in Whites.

Pathophysiology

Rhabdomyolysis occurs in patients with polymyositis due to direct damage caused by the cellular immune response that develops as a result of abnormal activation of cytotoxic T cells (CD8) and macrophages with some involvement of type B lymphocytes and dendritic cells.

The release of inflammatory mediators in circulation by the cells such as cytokines and interleukins can cause indirect damage. 

There is a significant increase in pro-inflammatory cytokine IL-21, both in the muscle and serum of affected patients, as well as increased expression of IL-21 receptors (IL-21R) in damaged muscle fibers in these patients [16]. T helper type 1 response due to the release of cytokines and T helper type 17 response due to its pro-inflammatory mediators are other mechanisms that cause polymyositis [17,18].

Certain cytokines such as IL-1alpha and IL-17 upregulate the nuclear factor kappa B signaling pathway to increase MHC-1 class expression. Nuclear factor kappa B also damages myofibrils by affecting the myocytes' differentiating ability negatively [19]. 

Other causes for polymyositis include damage to vascular endothelium leading to extravasation of inflammatory mediators from circulation as well as the involvement of humoral immune response. 

Histopathology

Polymyositis is a chronic inflammatory disease hence a biopsy will show multiple small foci of inflammatory and necrotic changes and regenerative nodules. In the early stage histopathology of polymyositis will show endomysial mononuclear infiltrate consisting of mostly CD8 T cells and macrophages along with necrotic myofibrils. In the late stage changes include occluded capillaries due to inflammatory changes caused by endothelial damage and increased deposition of connective tissue and extracellular matrix. 

History and Physical Examination

A good detailed history must be obtained to diagnose polymyositis in the early stage. Family history and medication history should also be obtained. Polymyositis is a relatively challenging diagnosis. The following should be included in the history to make an accurate diagnosis: 

• Gradual onset of muscle weakness with or without pain

• Presence of multiple joint pain

• Difficulty in standing up from the sitting posture. Difficulty in combing hair, inability to raise arms above the head, and holding the neck in an upright posture.

• When there is systematic spread there can be dysphagia due to pharyngeal or esophageal muscle involvement, breathing difficulty, or chest tightness due to infiltrative cardiomyopathy or pericarditis.

Presenting features

Polymyositis is a progressive disease with symmetric involvement of shoulder and pelvis muscles as well as neck flexors [2]. There can be weakness of the muscles with or without pain. Hip extensors can be involved in some patients making it difficult for the patients to climb stairs or to change their posture. Patients may complain of the inability to raise their arms above their head or to get up from seated position. Disease progression to distal muscles can result in difficulty in writing and playing musical instruments. 

They can have constitutional symptoms such as low-grade fever, anorexia, arthralgia, and weight loss. Polymyositis can cause interstitial lung disease which will produce shortness of breath and dry cough [20]. The patients can have chest tightness and exertional dyspnea due to restrictive cardiomyopathy. Constipation or bloating can occur due to gastrointestinal involvement. Tightening and discoloration of fingers also can occur due to Raynaud phenomenon.

During physical examination, a complete motor and sensory examination of affected muscles is carried out. In patients with polymyositis, the sensory examination is usually normal. Motor examination shows a decrease in power in the affected muscles. Tendon reflexes are lost in patients with severe muscular atrophy.

Patients who have restrictive polymyositis can present with limited mobility of truncal muscles which leads to camptocormia [21]. The involvement of nasopharyngeal muscles can cause nasal speech. If interstitial lung disease is present, crackles can be heard at the lung bases. 

If the polymyositis is associated with malignancy, then features of that particular neoplasia can be seen e.g., lymphadenopathy in non-Hodgkin lymphoma. Skin rashes will be found in the presence of other autoimmune disorders such as mixed connective tissue disorder.

Evaluation

In evaluating patients with suspected polymyositis a multi-modal approach is taken. It consists of hematologic and serologic testing, imaging, electromyography, nerve conduction studies, and biopsy findings. A full blood count (FBC) can show an elevated lymphocyte count in the majority of the patients and frequently thrombocytosis is also present. The Erythrocyte sedimentation rate (ESR) is elevated due to chronic inflammation. Serum creatine kinase (CK) levels can be very high. The levels can be up to 50 times the normal range (22 to 198 units/liter), indicating myocyte damage due to chronic inflammation. Serial serum creatine kinase monitoring can be of great clinical use to monitor disease progression. 

Elevation of multiple antibodies is not uncommon in patients with polymyositis. Antinuclear antibody (ANA), can be positive in about 33% of the patients with polymyositis. If ANA turns out to be positive, then specific antibody testing for anti-signal recognition particle (SRP) in the serum, is carried out. 

Patients with polymyositis will have abnormal electromyography (EMG) findings. There will be varying amplitude and velocity of the membranous action potential and fibrillation in potentials due to membrane irritability. 

An MRI is a useful investigation for the diagnosis of polymyositis. A biopsy can also be done which will show perivascular and endomysial mononuclear infiltrates and areas of necrosis staining pink due to high eosin stain [22]

If the patient has dysphagia, a barium swallow can be performed. In patients with lung disease, pulmonary function tests can be carried out. If polymyositis has caused damage to heart muscles, then an electrocardiogram and echocardiography can be performed.

Management

Polymyositis can be treated with a combination of different non-pharmacological and pharmacological modalities. Pharmacological treatment includes the use of corticosteroids. Methylprednisolone and prednisone are the most commonly used corticosteroids for the treatment of polymyositis. The starting dose of prednisolone is 1mg/kg of prednisone a day. The steroids cannot be withdrawn suddenly. They are tapered off gradually.

The second-line of treatment includes the use of immune modulators such as azathioprine, methotrexate, and cyclosporine in patients who either fail to respond to steroids or develop severe side effects due to the steroids. 

Cyclophosphamide is an immune-modulator that works efficiently in patients with the involvement of the lungs [23].

In patients with chronic refractory polymyositis, intravenous immunoglobulins can be used. A study by Cherin et al [24] showed improvement in around 70% of the patients with the use of intravenous immunoglobulins. 

Patients with dysphagia due to esophageal involvement also show significant improvement with intravenous immunoglobulins [25].

There are certain biologics such as infliximab and etanercept, that have been used in treating refractory cases of polymyositis [26]. Other therapeutic options include tacrolimus, a calcineurin inhibitor, with simultaneous use of prednisolone [27]. Mycophenolate mofetil and the anti-CD20 monoclonal antibody rituximab have been found to be useful in treating refractory cases of polymyositis.

Non-pharmacological treatment includes physical therapy of the involved muscles to prevent disuse atrophy. The patients need supervised resistive strength training exercises/activities [28]. Their diet should be rich in proteins that help in muscle building.

Differential Diagnosis

When a patient presents with myopathy, the following conditions have to be excluded to make a definite diagnosis:

1. Electrolyte imbalance-induced myopathy. Electrolyte imbalance can occur due to the loss of potassium, phosphate, or magnesium from the body. Hypokalemia/Hypophosphatemia can cause muscle cramps and aches which mimic polymyositis.

2. Hormonal disorders. Endocrinological disorders such as hypothyroidism or hyperthyroidism, diabetes mellitus, and metabolic syndrome can produce proximal musculature weakness just as in polymyositis. 

3. Other autoimmune disorders. Other autoimmune disorders must be excluded before a diagnosis of polymyositis is made. The most common differential is dermatomyositis which can be easily differentiated by the dermatologic presentation. Other disorders that are to be kept in mind before making the diagnosis of polymyositis are scleroderma, iatrogenic myopathies, myasthenia gravis, mixed connective tissue disorder, systemic lupus erythematosus (SLE), and myositis-induced myopathies. 

4. Chronic steroid use. A history of chronic steroid use should be obtained to exclude steroid-induced myopathy or Cushing syndrome.

5. Fibromyalgia or polymyalgia rheumatica (PMR). Patients with fibromyalgia or polymyalgia rheumatica can complain about muscle pain and weakness. Amyotrophic lateral sclerosis should be excluded because it can also produce myopathy.

6. Drugs with a tendency to produce myopaty. Certain drugs can produce myopathies. All drugs having a tendency for myopathy should be kept in mind. These include chloroquine/primaquine, statins, azathioprine, alcohol derivates, e.g., ethanol, antimetabolites (vincristine), and anti-fungal agents.

Prognosis

Polymyositis being a chronic disease, in the long run, it is associated with a grave prognosis. It produces disability and affects the quality of life of the patient. It is associated with a 10% mortality rate, especially in those who develop cardiac dysfunction or malignant conditions [29]. Majority of the patients usually respond to steroid therapy. This disease has the worst prognosis in older females, Blacks and patients having refractory disease, and patients who have systematic involvement.

Complications

Polymyositis has been found to be associated with increased morbidity and mortality due to its associated comorbid conditions such as involvement of major vessels, heart, lung, and gastrointestinal tract. The risk of myocardial infarct is about 2.2% in patients with polymyositis as compared to the general population [30]. There is a risk of developing cancer within a year of diagnosis of polymyositis [31]. The presence of a high neutrophil/lymphocyte ratio in patients above the age of 60 years greatly increases the risk of having carcinoma of lung/bladder or non-Hodgkin lymphoma [32].

In the late stage of the disease, polymyositis can affect the distal musculature of the esophagus in up to 70% of the patients leading to inability to swallow, as well as regurgitation problems which can cause aspiration pneumonia [33]. Lung involvement can increase the mortality rate and it can have an adverse impact on the quality of life. Polymyositis, in females of the child-bearing age group, can cause fetal loss.

Polymyositis can produce a hypercoagulable state in the plasma leading to an increased incidence of thromboembolism [34]. Polymyositis can increase the risk of the development of amyotrophic lateral sclerosis [35]. The risk of osteoporosis is also increased in patients with polymyositis [36].

References

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