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Paraneoplastic Myopathy

Paraneoplastic Dermatomyositis

Paraneoplastic dermatomyositis (DM) is an inflammatory myopathy characterized by proximal muscle weakness and pathognomonic skin manifestations occurring in association with an underlying malignancy. It is considered a paraneoplastic syndrome when the inflammatory response in muscle and skin is triggered by an immune reaction to tumor antigens that cross-react with host tissues.

Epidemiology

Paraneoplastic dermatomyositis (DM) is more common in adults over 50 years of age. About 15–25% of adults with DM have an associated malignancy, with the highest cancer risk during the first year after diagnosis. The incidence of cancer in patients with DM is significantly higher than in the general population. Common associated malignancies include ovarian, lung, pancreatic, stomach, colorectal, and breast carcinomas, as well as non-Hodgkin lymphoma.

In paraneoplastic dermatomyositis, a muscle biopsy typically reveals perifascicular atrophy, a hallmark finding. There are also perivascular and perimysial inflammatory infiltrates, primarily composed of CD4+ T cells and B cells. Deposition of complement membrane attack complex (MAC) in capillaries contributes to vascular injury and muscle ischemia. A skin biopsy may reveal interface dermatitis, characterized by basal layer vacuolization, perivascular inflammation, and dermal mucin deposition.

Pathophysiology

The pathophysiology of paraneoplastic dermatomyositis is not fully understood. However, it is likely to involve autoimmune cross-reactivity, where the immune system targets tumor-associated antigens that resemble proteins found in muscle and skin. Humoral and complement-mediated vascular injury, characterized by antibody and complement deposition in capillaries, results in microangiopathy and tissue damage. Additionally, interferon signaling and upregulation of MHC class I on muscle fibers may further drive immune-mediated injury.

Clinical Manifestations

Paraneoplastic dermatomyositis presents with characteristic skin and muscle symptoms. Common cutaneous findings include a heliotrope rash (violaceous discoloration of the eyelids with periorbital edema) and Gottron’s papules over the knuckles, elbows, and knees. Patients may also exhibit Gottron’s sign, shawl sign, V-sign rashes, mechanic’s hands, and psoriasis-like scalp lesions.

Muscle involvement typically includes symmetric proximal weakness affecting the shoulders and hips, leading to difficulties with activities such as climbing stairs or lifting arms. Myalgias may occur, and some patients experience dysphagia due to the involvement of pharyngeal muscles. Systemic features can include interstitial lung disease, arthralgias, Raynaud phenomenon, and, more rarely, cardiac involvement.

The prognosis of paraneoplastic dermatomyositis largely depends on the underlying malignancy. In some cases, treating the cancer can result in a complete resolution of dermatomyositis symptoms. However, this form is often more resistant to immunosuppressive therapy than idiopathic DM. Early cancer detection and long-term follow-up are essential, as malignancy may appear months or even years after symptom onset.

Paraneoplastic Polymyositis

Paraneoplastic polymyositis (PM) is a type of idiopathic inflammatory myopathy characterized by symmetric proximal muscle weakness and muscle inflammation that occurs in association with an underlying malignancy. It is considered a paraneoplastic syndrome when a tumor triggers immune-mediated muscle inflammation without direct tumor invasion or treatment-related effects.

Epidemiology

Paraneoplastic PM is less common than paraneoplastic dermatomyositis but still occurs more frequently in adults over the age of 50. Around 5–10% of patients with PM are found to have an associated malignancy. The cancer risk is highest in the first year after PM diagnosis and decreases over time. Malignancies most commonly associated with PM include lung, bladder, and non-Hodgkin lymphoma, although the overall cancer risk is lower than in dermatomyositis.

In paraneoplastic polymyositis, a muscle biopsy typically reveals endomysial infiltration by CD8+ cytotoxic T cells and the invasion of non-necrotic muscle fibers by inflammatory cells, which is a hallmark feature. Muscle fiber necrosis and regeneration are commonly seen. Unlike dermatomyositis, perifascicular atrophy is absent, which helps in distinguishing between the two conditions. A skin biopsy is not relevant in PM, as it typically lacks cutaneous manifestations.

Pathophysiology

The pathogenesis of paraneoplastic PM is thought to involve autoimmune cross-reactivity, where immune responses to tumor antigens target skeletal muscle fibers. CD8+ T-cell–mediated cytotoxicity plays a central role, involving the infiltration and destruction of muscle fibers that express MHC class I molecules. Additional mechanisms may include cytokine activation and the upregulation of immune checkpoints, which contribute to sustained inflammation and muscle damage.

Clinical Manifestations

Paraneoplastic polymyositis primarily presents with muscle-related symptoms and systemic features. The cardinal symptom is symmetric proximal muscle weakness, especially affecting the shoulder and pelvic girdles. Patients often experience difficulty climbing stairs, lifting objects, or rising from a seated position. Myalgia and muscle tenderness can vary, and dysphagia may occur due to the involvement of pharyngeal and esophageal muscles. Unlike dermatomyositis, paraneoplastic PM does not have skin findings, and systemic symptoms may include fatigue, weight loss, low-grade fever, and occasionally interstitial lung disease or cardiac involvement.

Elevated serum muscle enzymes, especially creatine kinase (CK), are common. EMG shows a myopathic pattern with fibrillations and low-amplitude motor unit potentials. Muscle biopsy confirms endomysial inflammation and invasion of muscle fibers by CD8+ T cells. Myositis-specific autoantibodies may be present, including anti-synthetase antibodies, although they are less frequently associated with cancer than anti-TIF1-γ in DM. Cancer screening is essential and should be guided by age, sex, and risk factors, using imaging and other appropriate tests.

Treatment of the underlying malignancy Control or removal of the tumor often leads to improvement or resolution of myositis symptoms.

Immunosuppressive therapy Corticosteroids are the first-line treatment. Steroid-sparing agents, such as methotrexate or azathioprine, are commonly used. IVIG, mycophenolate, or rituximab may be considered in refractory cases.

Supportive management Physical therapy to maintain mobility and prevent contractures Nutritional support, particularly in patients with dysphagia

The prognosis in paraneoplastic PM is closely linked to the underlying cancer. In some patients, effective cancer treatment results in marked improvement of muscle symptoms. However, paraneoplastic PM often responds less well to immunosuppression than idiopathic PM. Early detection of malignancy and prompt treatment are crucial for achieving better outcomes. Long-term monitoring is needed, as cancer may be diagnosed months or years after PM onset.

Necrotizing Autoimmune Myopathy (NAM)

Necrotizing autoimmune myopathy is a rare, severe inflammatory myopathy characterized by widespread muscle fiber necrosis with minimal or no inflammatory cell infiltration. It can occur as a paraneoplastic syndrome or independently and is often immune-mediated.

Epidemiology

NAM can affect adults of any age but is most commonly diagnosed in middle-aged individuals. A subset of NAM cases is associated with malignancy, although this association is less frequent than in dermatomyositis. NAM is also linked to statin use and certain autoantibodies.

Muscle biopsy shows widespread necrosis and regeneration of muscle fibers with very sparse inflammatory infiltrates. Unlike polymyositis, there is little or no endomysial inflammation. The predominant pathology is muscle fiber necrosis without perifascicular atrophy. Complement deposition may be seen on muscle capillaries, indicating immune-mediated injury.

Pathophysiology

NAM is thought to be mediated by autoantibodies targeting muscle antigens, leading to complement activation and muscle fiber necrosis. Key autoantibodies associated with NAM include anti-SRP and anti-HMGCR. Complement-mediated membrane attack complex deposition on muscle fibers causes direct muscle injury.

Clinical Manifestations

NAM primarily presents with severe, symmetric proximal muscle weakness, often progressing rapidly. Patients may have difficulty with activities such as climbing stairs or lifting objects. Myalgias and muscle tenderness are common. Dysphagia and respiratory muscle involvement can occur in severe cases. Systemic symptoms like fatigue and weight loss may also be present. Unlike dermatomyositis, NAM lacks skin manifestations.

Diagnosis is based on clinical features, elevated muscle enzymes (especially CK), electromyography showing myopathic changes, and characteristic muscle biopsy findings of necrosis with minimal inflammation. Testing for myositis-specific autoantibodies such as anti-SRP and anti-HMGCR aids diagnosis. Cancer screening is recommended when NAM is suspected to be paraneoplastic.

Treatment includes immunosuppressive therapy such as high-dose corticosteroids, often combined with steroid-sparing agents like methotrexate or azathioprine. Intravenous immunoglobulin (IVIG) and rituximab may be effective in refractory cases. Management of an underlying malignancy, if present, is crucial. Supportive care with physical therapy is important to preserve muscle function.

Prognosis varies but is generally guarded, especially in cases of paraneoplastic disease or when treatment is delayed. Some patients respond well to immunotherapy, while others have persistent weakness. Early recognition and treatment of both the myopathy and any underlying cancer improve outcomes. Long-term monitoring is necessary due to potential relapses and delayed cancer diagnosis.