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Chapter: Essential Clinical Immunology: Experimental Approaches to the Study of Autoimmune Rheumatic Diseases

Polymyositis: Epidemiology, Etiology, Pathogenesis, Clinical Features, Treatment, Animal Models

Polymyositis (PM) is an inflammatory muscle disease characterized by injury and death of muscle cells and resulting in severe weakness. Polymyositis is considered to be an autoimmune disease based on the pres-ence of autoantibodies with characteristic specificities, including those reactive with tRNA synthetases.

POLYMYOSITIS

Introduction and Epidemiology

Polymyositis (PM) is an inflammatory muscle disease characterized by injury and death of muscle cells and resulting in severe weakness. Polymyositis is considered to be an autoimmune disease based on the pres-ence of autoantibodies with characteristic specificities, including those reactive with tRNA synthetases. In addition, infiltration of T cells, predominantly CD8+ cytotoxic T cells, may contribute directly to muscle damage. PM is a rare disease and only a few epidemiological studies have been published. The reported incidence ranges between two and eight new cases per mil-lion people per year.

Etiology and Pathogenesis

The idiopathic inflammatory myopa-thies, including PM, are believed to be immune-mediated processes possibly triggered by environmental factors in genetically susceptible individuals. This hypothesis is based on the recognized association with other autoimmune and collagen vascular diseases, the preva-lence and type of circulating autoanti-bodies, animal models, immunogenetic observations, specifics of the inflamma-tory changes in muscle, and the treat-ment response to immunosuppressive agents. Autoantibodies associated with PM include the anti-tRNA synthetase antibodies (anti-Jo-1 and others) as well as antibodies directed against the sig-nal recognition particle. In PM, CD8+ cytotoxic T cells invade muscle fibers that express MHC class I antigens, lead-ing to fiber necrosis via the perforin pathway.

Clinical Features

The main symptoms of PM are weakness affecting primarily the proximal muscles. The onset is typically subacute, occurring over several weeks, with patients com-plaining of increasing fatigue in rising from a chair, lifting their arms, climbing steps, or combing their hair. The neck extensor muscles may be involved caus-ing difficulty in holding up the head. In severe advanced cases, the respiratory and oropharyngeal muscles are involved causing dysphagia and respiratory dif-ficulties. Myalgias are less frequent than muscular weakness, and when present, accompany the weakness. The most com-mon clinical signs are decreased strength in the proximal muscles, contractures, and late in the course of the disease, muscular atrophy, which occurs in up to 40 percent of cases. Dysphagia occurs in one-third of cases and is due to involvement of the oropharyngeal muscles or involvement of the striated muscle fibers of the upper esophagus. Pulmonary symptoms are due to weakness of the thoracic muscles or interstitial lung disease. Fibrosis is radiologically demonstrated in 5‚Äď10 per-cent of cases and is often associated with anti-tRNA synthetase antibodies such as anti-Jo-1.

Treatment of Polymyositis

Glucocorticoids are the standard first-line medication for patients with idiopathic inflammatory myopathy. Initially, predni-sone is given in a single dose of 1 to 2 mg/kg per day. Regular evaluations of muscle strength and serum enzymes should be performed during treatment. Ideally, the initial steroid dosage is maintained until strength and creatine kinase values have returned to normal and have remained normal for four to eight weeks and then tapered. If a patient fails to respond to glucocorticoid therapy or if a patient has had some improvement but the level of strength has reached a plateau, additional therapy with either the immunosuppres-sive agent azathioprine or methotrexate is added. Another therapeutic option is intra-venous immune globulin, which is being used increasingly to treat inflammatory myopathies. This therapy is associated with little toxicity but is extremely expensive. Controlled trials involving larger numbers of patients are needed to prove a benefit for this and other therapies in PM.

Animal Models of Polymyositis

Several animal models have been devel-oped that may prove useful for understand-ing the pathogenesis of PM. Experimental autoimmune myositis (EAM) can be induced by immunization of rodents with skeletal muscle homogenate and adju-vant. Similarly, Lewis rats immunized with purified skeletal muscle myosin develop EAM with the same pattern and severity as EAM induced by whole-rabbit skeletal-muscle homogenate. Multiple inflammatory lesions are detected histo-pathologically in various muscle groups in animals immunized with either prepa-ration. Dendritic cells presenting pyruvate kinase M1/M2 peptide 464-472 to T cells have also been effective in inducing EAM in BALB/c mice, with >40 percent of the mice developing pathological changes in skeletal muscle similar to those seen in human PM.

PM can also be induced in mice by viral infection. Intraperitoneal inoculation of Coxsackie B1 virus, Tucson strain, into young mice can result in proximal hind-quarter weakness that persists for more than ten weeks. The myositis persists long after the virus is cleared and in the pres-ence of neutralizing antibody, suggesting that the immunological response is con-tributing to pathology.


A possible murine model of inflamma-tory myositis has resulted from a genetic deficiency in a member of the synapto-tagmin family, comprising Ca2+ sensors involved in cell membrane fusion. Syt VII is a ubiquitously expressed synaptotagmin previously implicated in plasma membrane repair and Trypanosoma cruzi invasion, events mediated by the Ca2+-regulated exocytosis of lysosomes. Mice that are Syt VII deficient have an inflammatory myopathy, with muscle-fiber invasion by leukocytes and endomysial collagen depo-sition. This pathological picture is associ-ated with elevated creatine kinase release and progressive muscle weakness as well as a strong ANA response.

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Essential Clinical Immunology: Experimental Approaches to the Study of Autoimmune Rheumatic Diseases : Polymyositis: Epidemiology, Etiology, Pathogenesis, Clinical Features, Treatment, Animal Models |


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