Continuing Education Activity

Polymyositis, a relatively uncommon autoimmune disorder, develops due to abnormal activation of cytotoxic T lymphocytes (CD8 cells) and macrophages against muscular antigens that result in rhabdomyolysis and ultimately presents as a proximal myopathy. This activity outlines the evaluation and treatment of polymyositis and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Review the etiology of polymyositis.
• Describes the appropriate evaluation process for polymyositis.
• Outline the management options for polymyositis.
• Summarize the interprofessional team strategies for improving care coordination and communication to enhance the care of patients with polymyositis.

Introduction

Idiopathic inflammatory myopathies involve four major subtypes that include polymyositis, dermatomyositis, inclusion body myositis, and necrotizing myopathy. Bohan and Peter categorized myopathies into 7 classes.[1] Polymyositis, an autoimmune and chronic inflammatory myopathy, is characterized by symmetrical proximal muscle weakness due to the involvement of endomysial layers of skeletal muscles versus dermatomyositis, which involves the perimysial layers of muscles along with dermatological presentations.[2] 

Polymyositis develops over the months as compared to inclusion body myositis (IBM), which is a slowly progressive chronic myopathy developing in older individuals over a period of months to years with more severe symptoms. IBM develops secondary to either an autoimmune reaction or due to a degenerative process as a result of a persistent retroviral infection such as human T-cell leukemia virus type 1 (HTLV-1).[3] Being an autoimmune disorder, polymyositis, a rheumatological disease, requires long-term treatment with steroids or immunomodulators along with the treatment of the underlying etiological factors. Although this is a rare disorder, polymyositis should be a part of the differential diagnosis of patients experiencing unexplained muscle weakness as the failure to make a diagnosis can have a significant impact on the patient's quality of life due to severe complications.

Etiology

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

Different cytokines, including interleukins, tumor necrosis factor (TNF), etc. play an important role in causing rhabdomyolysis. It mostly affects individuals already suffering from some kind of systematic disease due to viral infections, malignancies, or other autoimmune disorders. The commonly responsible viruses for polymyositis are the retroviruses human immunodeficiency virus (HIV) and HTLV1, and hepatitis C virus that possibly cause this inflammatory muscle degeneration by causing endomysial damage leading to edematous swelling and nodular mass formation in the myocytes.[6][7] 

Coxsackievirus is another reason for this autoimmune disorder due to the abnormal functioning of major histocompatibility complex (MHC) secondary to the release of the cytokines after damaging the intima and endothelium of blood vessels.[8] Another important etiological factor for polymyositis-induced rhabdomyolysis is an underlying malignancy, e.g., lung carcinoma, genitourinary malignancy or lymphomas, etc. The presence of polymyositis also increases the possibility of having carcinoma in 2-5 years after the diagnosis, especially non-Hodgkin lymphoma. It has the highest risk of development followed by lung carcinoma and bladder carcinomas.[9] 

Other causes include the presence of certain HLA variants (A1, B8, DR3), the presence of another autoimmune disease such as celiac disease,[10] and 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. A study reported that 24% of patients on statin therapy developed polymyositis.[11]

Epidemiology

Autoimmune disorders are the leading cause of increased mortality among the middle-aged population in the United States with varying incidence rates.[12] Polymyositis rarely presents in childhood and usually affects people above the age of 20 years. Dermatomyositis, however, has a bimodal age distribution affecting the population between 5 to 15 years and 45 to 60 years.[13] 

The chances of disease development are almost double in women than in men, which is exactly the opposite of IBM. In the USA population, the rate of development of this autoimmune disorder is about 0.5 to 8.4 cases per 100,000 individuals. Having ethnic variation, it has been more commonly reported in Blacks than in Whites.

Pathophysiology

The following pathophysiological mechanisms have been proposed to define the main reason for rhabdomyolysis occurring in polymyositis. 

Direct damage due to 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.

Indirectly, damage can happen due to the release of inflammatory mediators in circulation by the cells such as cytokines and interleukins. A study reported a significant increase in pro-inflammatory cytokine IL-21, both in the muscle and serum of affected patients, along with the increased expression of IL-21 receptors (IL-21R) in damaged muscle fibers in these patients.[14] T helper type 1 (Th-1) response due to the release of cytokines (TNF, interferon-gamma, IL-12) and T helper type 17 (Th17) response due to its pro-inflammatory mediators (IL-17, IL-22, and IL-6) are other potential pathogenic mechanisms for causing polymyositis.[15][16] 

In addition to causing direct damage, certain cytokines such as IL-1alpha and IL-17 also upregulate the nuclear factor kappa B (NF-kappaB) signaling pathway to increase MHC-1 class expression. NF-kappaB also damages myofibrils by affecting the myocytes' differentiating ability negatively.[17] 

Other possible pathological 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 depending on the presence of certain antibodies.

Histopathology

Polymyositis is a chronic inflammatory disease, so multiple small foci of inflammatory and necrotic changes and regenerative nodules can be seen on biopsy. Histopathological findings of polymyositis show endomysial mononuclear infiltrate consisting of mostly CD8 T cells and macrophages along with necrotic myofibrils in the early-stage. Late-stage changes include occluded capillaries secondary to inflammatory changes caused by endothelial damage and increased deposition of connective tissue and extracellular matrix. Polymyositis can be differentiated from inclusion body myositis due to the presence of intracytoplasmic inclusion bodies in IBM, and from dermatomyositis due to perimysial infiltrates of CD4 cells as well as B lymphocytes.

History and Physical

The first step to diagnose polymyositis in the early stage is to get a detailed history, including family history, medication history, and any antecedent infections. Polymyositis is a relatively challenging diagnosis due to the absence of dermatological findings when compared to dermatomyositis. The following points should be asked in detail to make an accurate diagnosis. 

1. Gradual onset of myopathy with or without associated myalgia
2. Presence of joint pains to rule out other autoimmune disorders
3. The pelvic girdle is involved more commonly as compared to the shoulder muscles, so inquire about the difficulty in standing up from the sitting posture. Patients with upper body involvement can have difficulty in hair combing, inability to raise arms above head, and holding the neck in an upright posture.
4. Patients having the systematic spread can complain of dysphagia due to pharyngeal or esophageal muscle involvement, breathing difficulty, or chest tightness due to infiltrative cardiomyopathy or pericarditis, etc.

Presenting features

The hallmark of polymyositis is a progressive disease with symmetric involvement of proximal girdle muscles (shoulder and pelvis muscles) and neck flexors that can be painful at times.[2] Hip extensors can be involved in some patients making it difficult for them to climb stairs or to have posture change. Patients may complain of the inability of overhead abduction or to get up from the seated position. Disease progression to distal muscles can result in abnormal fine movements such as writing and playing musical instruments. Constitutional symptoms include low-grade fever, anorexia, arthralgia, and weight loss. Polymyositis can cause interstitial lung disease (ILD), especially in anti-Jo-1 positive patients, presenting as shortness of breath and dry cough.[18] Other presenting complaints are chest tightness and exertional dyspnea due to restrictive cardiomyopathy, constipation, or bloating due to gastrointestinal involvement and tightening and discoloration of fingers due to Raynaud phenomenon.

The physical examination must include a complete motor and sensory examination of affected muscles. Though the sensory examination is usually normal in these patients, motor examination reveals a decrease in power in the affected portion depending on disease severity with lost tendon reflexes in severe muscular atrophy. Patients with restrictive polymyositis can present with limited mobility of truncal muscles, especially abnormal flexion that is called camptocormia.[19] The involvement of nasopharyngeal muscles can cause nasal speech, while, in the presence of ILD, crackles can be heard at the lung bases. If polymyositis is associated with any malignancy, then features of that particular neoplasia can be seen e.g., lymphadenopathy in non-Hodgkin lymphoma. Skin rashes can be found in the presence of other autoimmune disorders such as mixed connective tissue disorder.

Evaluation

The multi-modal approach consisting of hematologic and serologic testing, imaging, electromyography, nerve conduction studies, and biopsy findings is used to evaluate a patient with suspected polymyositis. A complete blood count (CBC) can show an elevated lymphocyte count in the majority of the patients and frequently thrombocytosis as well. Erythrocyte sedimentation rate (ESR) can be elevated due to chronic inflammation. Serum creatine kinase (CK) levels can be as high as up to 50 times the normal range (22 to 198 units/liter), indicating myocyte damage due to chronic inflammation. It can be of great clinical use to monitor disease progression by having serial examinations and CK monitoring.

Multiple antibodies can be elevated in polymyositis, such as a non-specific antinuclear antibody (ANA), which can be positive in around 33 percent of the patients with polymyositis. If ANA turns out to be positive, then specific antibody testing is done to confirm PM, which is the anti-signal recognition particle (SRP) in the serum. The presence of anti-aminoacyl tRNA synthetases (ARS) antibodies can show the association of PM with an autoimmune syndrome know as the anti-synthetase syndrome. This is characterized by a group of varying physical presenting features such as inflammation-induced myopathy, joint pain, Raynaud's phenomenon, and fibrotic lung disease.[20] In the case of statin-induced PM, a unique 3-hydroxy-3-methylglutaryl coenzyme A reductase IgG immunoglobulin (anti- HMGCR) can be elevated.[21] 

Almost all the patients with PM will have abnormal electromyography (EMG) findings such as varying amplitude and velocity of the membranous action potential, and fibrillation in potentials due to membrane irritability, etc. A vital investigation to make a definitive diagnosis of myopathy is a magnetic resonance imaging (MRI) or EMG guided biopsy that shows perivascular and endomysial mononuclear infiltrates (cytotoxic T lymphocytes and macrophages) and areas of necrosis staining pink due to high eosin stain binding.[22]

Imaging studies such as MRI, computed tomography (CT) scan, or ultrasonography can be useful to locate an area of muscle damage and also to diagnose underlying malignancy. Whole-body magnetic resonance imaging is of utmost significance to exactly diagnose the damaged muscular area.[23] 

If the patient presents with dysphagia, a barium swallow can be performed. In the case of lung disease, pulmonary function tests (PFTs) can be done. If PM has caused damage to cardiomyocytes, then an electrocardiogram (EKG) and echocardiography can be performed.

Treatment / Management

Polymyositis is treated with a combination of different pharmacological and non-pharmacological modalities. Pharmacological treatment mainly includes corticosteroids. Prednisone and methylprednisolone are the most common corticosteroids used for polymyositis with a starting dose of 1mg/kg of prednisone a day. The steroids are tapered off gradually and not withdrawn suddenly. The second-line treatment option includes the use of immune-modulators (methotrexate, azathioprine, cyclosporine) in those patients who either do not respond to steroids or develop severe adverse effects due to steroids usage. Cyclophosphamide, an immune-modulator, works efficiently, especially in patients with the involvement of the pulmonary interstitium.[24] In the case of chronic refractory polymyositis, intravenous immunoglobulins (IVIG) can be used. A study showed improvement in around 70% of the patients after the use of IVIG.[25] 

IVIG also shows significant improvement in patients having dysphagia due to esophageal involvement.[26] Ceratin biologics such as infliximab and etanercept, have been used in treating refractory cases of PM.[27] Other therapies option include tacrolimus, a calcineurin inhibitor, that has proven to be beneficial in patients having a refractory disease with simultaneous use of prednisolone.[28] Mycophenolate mofetil and the anti-CD20 monoclonal antibody rituximab have also been found to be useful in treating refractory cases of polymyositis.

Patients with different systems involved must be evaluated by the concerned specialty e.g. cardiologist for cardiomyopathy, pulmonologist for ILD, a speech therapist for voice change, etc. Non-pharmacological treatment includes physical therapy of the affected muscles to prevent disuse atrophy. These patients must be advised to have supervised resistive strength training activities.[29] These individuals should be advised to have a diet rich in proteins that help in muscle building.

Differential Diagnosis

If a patient presents with myopathy, the following conditions must be excluded to make an absolute diagnosis.

1. Electrolyte imbalance-induced myopathy that can commonly occur due to the loss of potassium, phosphate, or magnesium from the body. Hypokalemia/Hypophosphatemia can cause muscle cramps and aches leading to a myopathic situation similar to PM.
2. Another important category that must be kept in the differential is endocrinological disorders, e.g., hypothyroidism or hyperthyroidism, diabetes mellitus, and metabolic syndrome, etc. These hormonal disorders can make proximal musculature weak, making the clinical presentation similar to PM.
3. Other autoimmune disorders should be ruled out to diagnose polymyositis. The most common differential is dermatomyositis that is easily differentiated by the dermatologic presentation and endomysial presentation on biopsy. Other disorders to keep in mind for making the diagnosis of PM are myasthenia gravis, mixed connective tissue disorder, systemic lupus erythematosus (SLE), scleroderma, iatrogenic myopathies, and myositis-induced myopathies (focal/giant cell myositis).
4. A history of chronic steroid use should be taken to exclude steroid-induced myopathy or Cushing syndrome.
5. Patients with a previous diagnosis of fibromyalgia or polymyalgia rheumatica (PMR) can complain about muscle pain and weakness. These patients must be carefully evaluated to exclude these causes. Amyotrophic lateral sclerosis (ALS) can cause myopathy, so it should be excluded as well.
6. Drugs can be an important cause of myopathies, so all the drugs having a tendency for myopathy should be kept in mind, such as statins, alcohol derivates, e.g., ethanol, antimetabolites (vincristine), azathioprine, chloroquine/primaquine, and anti-fungal agents.

Prognosis

Polymyositis, being a chronic disease, is associated with a grave prognosis in the long run. In addition to causing disability and affecting the quality of life of the patient, this disease has also been found to be associated with a 10% mortality rate, especially in those who also develop cardiac dysfunction or malignant conditions.[30] The majority of patients usually respond to steroid therapy. This disease has the worst prognosis in the patients having refractory disease, older females, Blacks, and patients having systematic involvement.

Complications

Although polymyositis is a rare disease, it has been found to be associated with increased morbidity and mortality due to its associated comorbid conditions, e.g., the involvement of major vessels or gastrointestinal tract, etc. Patients with polymyositis have about 2.2% risk of having myocardial infarction as compared to the general population.[31] Patients with polymyositis are most likely to be diagnosed with cancer within the first year following the diagnosis of polymyositis, so age and gender-specific evaluation for malignancy should be done in all the patients with PM.[32] According to a study, 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.[33]

Polymyositis affects the distal musculature of the esophagus in the late stage of disease in up to 70% of the patients leading to the inability to swallow, as well as regurgitation problems that can cause aspiration pneumonia.[34] The involvement of the lungs can increase the mortality rate due to having an adverse impact on the quality of life. The presence of PM in the females of the child-bearing age group can result in a fetal loss in the case of active disease.

PM can induce a hypercoagulable state in the plasma leading to the increased incidence of thromboembolism.[35] An increase in the risk of development of amyotrophic lateral sclerosis was also observed in a study in patients with PM.[36] Osteoporosis risk has been found to be elevated in patients with PM.[37]

Deterrence and Patient Education

Since polymyositis can cause multiple comorbid conditions, it is mandatory to properly guide the patients to lessen their suffering. The following points should be explained to patients to prevent future consequences.

1. Guide patients to prevent extreme cold weather conditions due to potential chances of cold-induced necrosis of extremities due to Raynaud phenomenon-induced vascular obliteration/spasm.
2. Patients with esophageal motility disorder should be educated to avoid lying down immediately after a meal.
3. Prophylactic supplements containing calcium and vitamin D should be started early to prevent disease or steroids induced osteoporosis.
4. Detailed information should be provided to the patient if there is a possibility of having any underlying malignancy in high-risk candidates such as older male patients having broad systematic involvement.[38]
5. The importance of physical training should be emphasized.

Enhancing Healthcare Team Outcomes

A strong clinician-patient relationship is mandatory to improve healthcare outcomes along with good communication among an interprofessional team, which includes a rheumatologist, neurologist, gastroenterologist, pulmonologist, a primary clinician, a physiotherapist, a dietician, and nurses. Without proper management, the morbidity and mortality from polymyositis are high. However, successful diagnosis and treatment at the initial stage can help patients live longer.