Polymyositis: A Case Report

Abstract

Inflammatory myopathies are a group of diseases whose common pathway is immune-mediated muscle damage, one of which is polymyositis.

The definition of polymyositis is controversial, with proponents advocating a definition based on immunohistochemical and histopathological findings in muscle biopsies, while other proponents advocate a definition based on clinical manifestations and histopathological findings.

Polymyositis is a quite rare disease that is clinically characterized by progressive proximal muscle weakness with a symmetric distribution. Within the diagnostic approach, laboratory studies show elevation of sarcoplasmic enzymes; nerve conduction tests are performed, which may aid in distinguishing myopathic causes of weakness from neuropathic disorders; and muscle biopsy is considered the gold standard to diagnose inflammatory myopathy and to distinguish the subclasses.

We report the case of a 61-year-old male patient who presented generalized symmetrical weakness, predominantly in the upper extremities, and dysphagia, whose laboratory studies, autoantibodies, and muscle biopsy were confirmatory of this entity.

Introduction

Ernst Leberecht Wagner first described Polymyositis in two publications in 1863 and 1887 [1]. The first diagnostic criteria were established in 1975 by Bohan and Peter (exclude all other myopathies, symmetric proximal muscle weakness, increase in serum muscle enzymes, abnormal electromyographic findings, abnormal muscle biopsy findings, and skin rashes, such as Gottron’s papules) [2] as an inflammatory myopathy whose etiology was not fully understood, it was associated with viral and parasitic infections and non-infectious agents like medications, foods, and biologic agents. It is considered a diagnosis of exclusion; therefore, multiple pathologies must be ruled out before diagnosis. We present a male patient who debuted with symmetrical upper limb weakness and dysphagia and whose laboratory and pathology studies were confirmatory of this rare disease.

Case presentation

A 61-year-old male patient arrived at the Emergency Room due to a three-week history of progressive generalized weakness and dysphagia of solids. The patient’s weakness predominantly affected the proximal upper limbs symmetrically. The patient had a medical history of type 2 diabetes mellitus treated with 12 units of insulin glargine once daily, diabetic neuropathy treated with gabapentin 300 milligrams once daily, hypertension treated with metoprolol 100 milligrams once daily and nifedipine 30 milligrams twice daily, and end-stage kidney disease on peritoneal dialysis.

Physical examination revealed proximal upper limb weakness, a Medical Research Council Scale (MRC) global strength of 21, diffuse decreased deep tendon reflexes (1+), and normal muscle tone and sensation. The patient was admitted to the hospital for an adequate diagnostic approach.

The laboratory tests showed leukocytosis of 16.89 10^3/uL (4.6 - 10.4 10^3/uL), but no apparent source of infection could be found (negative cultures). The patient's leukocytosis continued during the hospitalization. To rule out a leukemoid reaction, tumor markers were requested, of which carcinoembryonic antigen 10.2 ng/ml (0-3 ng/ml) and CA-19.9 (142.5 U/ml) (0-35 U/ml) were found to be elevated. A contrasted tomography scan was performed, which didn't show any significant findings. Bone marrow aspirations were taken, and no abnormalities could be found. Other relevant test results were an elevated aspartate transaminase of 208 U/L (10-40 U/L), alanine transaminase of 93 U/L (10-40 U/L), and creatine phosphokinase (CK) of 1521 U/L (26-308 U/L). Due to the cholestatic pattern (R Factor 0.2) found in the liver tests, a liver and bile duct ultrasound was performed; however, no abnormalities were found. Viral panels, including Hepatitis B Virus, Hepatitis C Virus, Human Immunodeficiency Viruses 1 and 2, Cytomegalovirus, and Epstein-Barr Virus, were non-reactive. The laboratory studies during hospitalization can be seen in Tables 1-3 and Figure 1.

Three days after hospital admission, the patient's upper limb weakness worsened to an MRC of 11, and his dysphagia worsened due to secretion mismanagement. The patient was admitted to the ICU with advanced airway management. A neuromuscular disease was suspected, so a lumbar puncture, nerve conduction velocities (NCV), and electromyography (EMG) were performed at week one of hospitalization. The cerebrospinal fluid (CSF) results were within normal parameters. NCV showed reduced amplitude in compound muscle action potential (CMAP) and nerve conduction failure consistent with axonal polyneuropathy. EMG showed increased activity, positive sharp waves, and fibrillation. During slight muscle contraction, the Motor Unit Action Potential (MUAP) was short duration, polyphasic, and with a small amplitude. These findings should not be present in a demyelinating polyneuropathy (Figure 2). Despite these findings, the ICU decided to use IV Immunoglobulin (24 gr/day) for five days without achieving clinical improvement. The patient developed sinus tachycardia and ventricular extrasystoles. The electrocardiogram (EKG) showed inversion of the T wave on the anterior leads (Figure 3), and his cardiac enzymes showed increased troponin I of 11 ng/ml (0.0 - 0.04 ng/ml). Therefore, management with antiarrhythmic and anti-ischemic drugs was started. Statins were withheld since the patient’s creatine phosphokinase kept rising.

An autoimmune disease was suspected, and antibodies were requested (Table 1). Laboratory tests showed a decrease in Complement C3 and positive anti-signal recognition particle antibodies. These findings suggested an inflammatory myopathy, so treatment with 1 gram of rituximab was initiated, and a biopsy of the anterior tibial muscle was taken. One week after rituximab, the patient showed significant improvement in strength (MRC 18). The muscle biopsy showed endomysial mononuclear and polymorphonuclear infiltration indicative of polymyositis (Figure 4).

Unfortunately, the patient continued on prolonged invasive mechanical ventilation; he developed fever, bilateral lung rattles, and increased oxygen requirements. Ventilator-associated pneumonia due to Stenotrophomonas Maltophilia was diagnosed, and treatment with trimethoprim-sulfamethoxazole was started. The patient’s clinical condition worsened, developing disseminated intravascular coagulation, non-variceal upper gastrointestinal tract bleeding, septic shock, multiple organ failure, and eventually death.

Discussion

Polymyositis (also known as Unverricht-Warner or Wagner-Unverricht syndrome) was first described in the XIX century by Ernst Leberecht Wagner, a German pathologist, and Heinrich Unverricht, a German internist [1]. It was described as a rare idiopathic inflammatory myopathy that was immune-mediated [3].

Polymyositis represents 5% of autoimmune myositis. Furst et al. reported an incidence in the U.S. (United States) of 0.4 to 1.0 per 100,000 person-years [4], and Wilson et al. reported a prevalence of 3.45 per 100,000 inhabitants [5]. Oddis et al. noted that the incidence is higher in black patients [6]. Usually, symptom onset is seen after the second decade of life, with an average age of 50 to 60. This disease is more common in women than in men (2:1). Accurate measurement of incidence and prevalence is challenging due to the diagnostic criteria’s limitations and the lack of inclusion of new myositis-specific autoantibodies [7].

Multiple factors have been identified as triggers of inflammatory muscle diseases. A viral etiology (Human T-lymphotropic virus-I, Cytomegalovirus, Influenza virus, Coxsackievirus types A and B, Echoviruses, Parvovirus B19, Hepatitis C virus, Hepatitis B virus, Polio virus, and Human Immunodeficiency Virus) has been proposed by the presence of virus particles and high-titer anti-viral antibodies in patient serum and muscle samples. There have also been case reports where parasitic infections (Toxoplasma gondii and Trypanosoma cruzi) have been associated with the development of inflammatory myopathies. This association was supported when parasites were found in the muscle lesions, with polymorphonuclear and CD8 T cell infiltration in the muscle biopsy. Furthermore, the patients' myositis symptoms improved after treatment with anti-parasitic drugs. Soft tissue infections by staphylococci, clostridia, and mycobacteria cause acute muscle inflammation but do not cause chronic, self-sustaining muscle inflammation. In Lyme disease, Borrelia burgdorferi has been detected between the muscle fibers, causing inflammation [7,8].

Noninfectious agents related to polymyositis are medications, foods, and biological agents, either as a consequence of a toxic reaction or as an immune-mediated mechanism. Some examples of these agents are D-Penicillamine, fibrates, statins, tiopronin, leuprolide acetate, interleukin-2, interferon-alpha, growth hormone, and fish poisoning (Ciguatera). Noninfectious environmental exposures associated with polymyositis are injections of bovine collagen and chronic graft-versus-host disease. In chronic graft-versus-host disease, the donor's T cells (the graft) view the patient's healthy cells (the host) as foreign and initiate an immune-mediated attack [8].

The pathophysiology of polymyositis is not completely understood, but autoimmune pathogenesis is strongly implicated. Normal muscle fibers do not express MHC (major histocompatibility complex) class I. Nonetheless, activated T cells apparently secrete multiple cytokines such as IFN-γ (interferon gamma), TNF (tumor necrosis factor), and HMGB1 (high mobility group box 1 protein), which induce the expression of MHC I in the sarcolemma of muscle fibers. This sarcolemma is surrounded by CD8+ cytotoxic T cells, forming the CD8-MHC class I complex. These lymphocytes are clonally expanded and release their perforin granules toward the muscle fiber, inducing myofiber damage and necrosis [9].

This MHC class I overexpression leads to endoplasmic reticulum stress through two unfolded protein response (UPR) and endoplasmic reticulum overload (EOR). UPR turns on endoplasmic reticulum sensors like inositol-requiring enzyme 1 (IRE-1), protein kinase R-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF-6) due to glucose-regulated protein 78 (GRP78). These sensors down-regulate the translational machinery and reduce protein accumulation in the endoplasmic reticulum. Also, UPR activation leads to cell death through the CCAAT/enhancer binding protein (C/EBP) and caspase-12, which mediates endoplasmic reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Alternatively, EOR creates a self-sustaining loop by turning on the nuclear factor-κB (NF-κB) pathway, which upregulates the expression of endogenous class I MHC. Thus, more MHC class I is accumulated in the sarcoplasmic reticulum of skeletal muscle fibers, and more NF-κB is activated [10].

The diagnosis of Polymyositis is based on the clinical manifestations, the elevation of sarcoplasmic enzymes (CK, aldolase, lactic dehydrogenase, and transaminases), electromyography, and muscle biopsy [8-11].

The clinical manifestations of polymyositis are progressive symmetrical muscle weakness that develops over weeks or months. The symmetrical weakness is more pronounced in the proximal muscle groups like the neck, shoulders, upper chest, back, arms, and lateral thighs. The lower esophageal sphincter may be affected, causing reflux. When the anal sphincter is affected, fecal incontinence can occur. In more severe cases, patients may develop difficulty swallowing when the throat muscles are affected, which can result in aspiration pneumonia, which can be extremely severe when the diaphragm and breathing muscles are also affected [11]. Fernandez et al. and Schaumburg et al. even reported heart block and cardiac arrhythmias in this disease [12].

CK is the most sensitive muscle enzyme and an indicator of the degree of muscle fiber injury. It is elevated in 80%-90% of cases and can increase up to 50 times the upper limit in active disease. However, it does not relate well to the clinical compromise. The values may decrease or normalize without significant clinical improvement or increase without clinical compromise [11].

EMG should always be considered an extension of the clinical examination since it can be misinterpreted. EMG findings include increased insertional activity, polyphasic, short, small MUAP with low amplitude and short duration, positive sharp waves, and high-frequency repetitive discharges with a low level of contraction. These changes are nonspecific but are useful in distinguishing myopathic causes of weakness from neuropathic disorders. It is also used for selecting appropriate muscles for biopsy.

Most myopathies usually affect the proximal muscles more than the distal muscles. Thus, routine nerve conduction and motor studies are usually normal. However, when the inflammatory myopathy severely affects the recorded muscle reductions and blocks in CMAP may be found. This is due to the fact that the CMAP is a summation of individual muscle action potentials, and these muscles may be affected by inflammatory myopathy [13].

A muscle biopsy is essential since it’s the gold standard for polymyositis diagnosis. The most representative findings are perivascular inflammation, constituted by macrophages and activated CD8+ T cells in muscle fibers, which are concentrated in multiple foci within the endomysium. MHC class I molecule expression is also found in muscle fibers [14].

There are no known specific autoantibodies associated with polymyositis. However, antibodies usually found in this disease are anti-ARS (anti-aminoacyl tRNA synthetase), anti-SS-A (anti-Sjögren’s syndrome-related antigen A), and anti-SRP (anti-signal recognition particle), with a prevalence of 29%, 12%, and 5%, respectively [15].

MRI (magnetic resonance imaging) is the imaging study of choice to assess soft tissues and muscles. MRI can assess inflammation, edema, calcifications, fatty replacement, atrophy, symmetry, and changes in the size of the muscles [16].

Ultrasonography with color Doppler imaging can assess the presence of myopathy. Affected muscles appear hypoechoic due to fatty infiltration and edema, with loss of definition and increased vascularity in the initial phases of the disease [17].

Ultrasonography can also be helpful for appropriate muscle biopsy sampling. The limitations of this study are that the abnormal findings in ultrasonography are not specific to inflammatory myopathies and that it’s an operator-dependent study [18].

Because polymyositis is a diagnosis of exclusion, other differential diagnoses must be excluded, like neuromuscular diseases and a wide variety of myopathies like dystrophic myopathies, metabolic myopathies, and mitochondrial myopathies, endocrine myopathies, infectious myopathies, drug-induced myopathies. These diseases are discussed in more detail in Table 4 [19-37].

High-dose glucocorticoids are the initial treatment for polymyositis. Oral prednisone 1 mg/kg is recommended, and in severe and rapidly worsening disease, intravenous methylprednisolone 1 g/dose once daily for 3-5 days may be used. Disease-modifying antirheumatic drugs (DMARDs) must be used to reduce the side effects of steroids and enhance their immunosuppressive effect. Some DMARDs used are mycophenolate mofetil, which inactivates inosine monophosphate dehydrogenase, an important enzyme in purine synthesis, which in consequence, inhibits T and B-cell proliferation (2-3 g per day divided into two doses), methotrexate, which inhibits folic acid and purine metabolism and adenosine signaling (10-25 mg per week orally or subcutaneously), and azathioprine, a purine analog that blocks T and B-cell proliferation (2-3 mg/kg per day) [38].

In patients with a rapidly worsening disease, severe life-threatening weakness, dysphagia with a high risk for aspiration, or resistant disease, intravenous immunoglobulin G (IVIG) is recommended (2 g/kg administered in divided doses over 2 to 5 days every four weeks for 3-6 months). When glucocorticoids and intravenous immunoglobulin are not effective, treatment escalation with rituximab, a monoclonal antibody against CD20, should be considered (1 g once every two weeks for two doses) [39].

Conclusions

Polymyositis is a rare disease whose etiology is not fully understood and requires a meticulous diagnostic approach. There have been few cases reported to date, so full documentation and publication are of paramount importance. This will help us improve the detection of this rare disease, achieve a better understanding of the factors associated with it, and improve its characterization. Also, we want to highlight that this pathology may have significant morbidity and mortality. Thus, the adequate interpretation of NCV and EMG is of paramount importance. Incorrect interpretation can lead to mismanagement, delayed treatment, disability, a high risk of complications related to management, and death.