Leukotriene receptor antagonist-associated Churg–Strauss syndrome

Overview

Leukotriene receptor antagonist-associated Churg–Strauss syndrome (LTRA-associated CSS), also known as eosinophilic granulomatosis with polyangiitis (EGPA), is a rare systemic vasculitis that affects small- to medium-sized blood vessels. It is characterized by asthma, high levels of eosinophils in the blood and tissues, and inflammation of blood vessels leading to damage in organs such as the lungs, skin, nerves, and heart. This syndrome has been associated with the use of leukotriene receptor antagonists (LTRAs), such as montelukast and zafirlukast, which are medications commonly used to manage asthma and allergic rhinitis.

Causes

The exact cause of Churg–Strauss syndrome remains unknown, but it is believed to involve an autoimmune response that leads to inflammation of the blood vessels. In cases associated with LTRA use, two main theories have been proposed:

• Unmasking hypothesis – LTRA medications may allow reduction or withdrawal of oral corticosteroids, which can unmask an underlying vasculitis that had been suppressed.

• Drug-induced hypothesis – LTRAs may directly trigger an immune-mediated vasculitic process in susceptible individuals.

Regardless of the mechanism, the presence of asthma and eosinophilia remains central to the diagnosis of LTRA-associated CSS.

Symptoms

Symptoms of LTRA-associated Churg–Strauss syndrome typically evolve through three phases:

• Allergic phase – characterized by asthma, allergic rhinitis, and sinusitis

• Eosinophilic phase – marked by elevated eosinophil counts and eosinophilic infiltration of organs such as the lungs and gastrointestinal tract

• Vasculitic phase – involving systemic inflammation of blood vessels, which can affect multiple organs

Common signs and symptoms include:

• New or worsening asthma

• Fatigue and weight loss

• Peripheral neuropathy (numbness, tingling, or weakness in hands and feet)

• Skin rashes or purpura

• Shortness of breath and cough

• Abdominal pain, nausea, or gastrointestinal bleeding

• Cardiac involvement (e.g., myocarditis or pericarditis) in severe cases

Diagnosis

Diagnosis of LTRA-associated Churg–Strauss syndrome is based on clinical criteria, laboratory findings, and exclusion of other causes. Key diagnostic steps include:

• Clinical history – including onset of asthma and recent use of LTRA medications

• Blood tests – showing eosinophilia (eosinophil count >10% of total white cells)

• ANCA testing – anti-neutrophil cytoplasmic antibodies may be positive, especially perinuclear ANCA (p-ANCA)

• Imaging – chest X-rays or CT scans showing pulmonary infiltrates

• Tissue biopsy – confirms vasculitis and eosinophilic infiltration of affected organs (e.g., skin, lung, or nerve tissue)

Diagnosis is typically made using criteria established by the American College of Rheumatology (ACR), requiring the presence of at least four of six defined features.

Treatment

Treatment of LTRA-associated Churg–Strauss syndrome aims to reduce inflammation, control symptoms, and prevent organ damage. Management includes:

• Discontinuation of LTRA medications – if suspected to be contributing to the disease

• Systemic corticosteroids – such as prednisone, which are the mainstay of therapy

• Immunosuppressive agents – including cyclophosphamide, azathioprine, or methotrexate for severe or refractory cases

• Biologic therapies – such as mepolizumab (anti-IL-5 monoclonal antibody) may be effective in reducing eosinophilic inflammation

• Monitoring and supportive care – including treatment for asthma, cardiac monitoring, and neurological support

Prognosis

The prognosis for individuals with LTRA-associated Churg–Strauss syndrome varies depending on the severity of organ involvement and the promptness of treatment. With early diagnosis and appropriate immunosuppressive therapy, many patients achieve remission and long-term disease control. However, delayed treatment or involvement of critical organs such as the heart or kidneys may lead to serious complications and increased mortality. Lifelong monitoring and follow-up with a rheumatologist or specialist are essential for managing relapses and medication side effects.