Eosinophilic granulomatosis with polyangiitis

Synonyms: eosinophilic granulomatosis with polyangiitis, allergic granulomatosis angiitis, granulomatous small-vessel vasculitis, eosinophilic granulomatosis with polyangiitis

What is EGPA?¹

EGPA (eosinophilic granulomatosis with polyangiitis), formerly known as Churg-Strauss syndrome, is a rare diffuse vasculitic disease affecting multiple organ systems, including the lungs, heart, kidneys, nervous system, skin, and gastrointestinal tract.¹

It can be distinguished from the other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), by its association with asthma, rhinosinusitis, and peripheral eosinophilia.¹

Epidemiology of EGPA¹

• EGPA was first described in 1951, based on autopsy findings. New classifications were proposed from the 1990s and, currently, the joint 2022 American College of Radiology and European Alliance of Associations for Rheumatology classification criteria for EGPA are used internationally.

• EGPA is a rare disease. The estimated prevalence is 1 to 3 per million adults worldwide.

• The reported mean age of onset is 38-54 years, with a median of 40. However, it has been reported at all ages, from as low as 4 to as high as 74.²

• 40% of adults and 25% of children with EGPA have a positive ANCA and both are characterised by high eosinophil and IgE levels.

• Children are more likely to have cardiomyopathy and pneumonic infiltrates.

Causes of EGPA (aetiology)²

The aetiology is unknown although allergies, infections, and medications have all been suggested as possible causes.¹ Drugs implicated have included mesalazine, propylthiouracil, methimazole, freebase cocaine, and leukotriene receptor antagonists.³

It has been postulated that T lymphocytes may undergo an oligoclonal expansion leading to an aberrant immune response.¹

Immunogenetic factors have been shown to predispose patients to EGPA.²

Diagnosing EGPA (diagnostic criteria)⁴

In 2022, the American College of Radiology and the European Alliance of Associations for Rheumatology developed a classification criteria for EGPA which included 7 criteria. Each criteria has a number of points associated with it and the diagnosis can be made if the cumulative score is greater than 6.

• A maximum eosinophil count of greater than 1×10⁹/L. (+5 points)

• Obstructive airways disease. (+3 points)

• Nasal polyps. (+3 points)

• Positive cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3-ANCA. (-3 points)

• Extravascular eosinophilic predominant inflammation. (+2 points)

• Mononeuritis multiplex/motor neuropathy not due to radiculopathy. (+ 1 points)

• Haematuria. (-1 point)

EGPA symptoms (presentation)¹⁵

Typically, although not always, EGPA has three distinct phases.

The prodrome commonly consists of nonspecific symptoms such as malaise, fever, weight loss, and migrating polyarthralgia (myalgia and polyarthralgia occur in between 37% and 57% of patients). A severe asthma often develops that does not respond to conventional treatment. Diffuse myalgia and polyarthralgia have been reported. Chronic rhinosinusitis and nasal polyps are very common, occurring in 47-93% and 62-77% of patients respectively; however, unlike in granulomatosis with polyangiitis (GPA), nasal granulomas, erosion, crusting, and epistaxis are not often seen.

The second phase develops when eosinophilic infiltrates occur in end organs, along with peripheral eosinophilia. Symptoms depend on the end organs affected.

The most prominent symptoms and signs during the second phase are:

• Pulmonary: This includes asthma, pneumonitis, and haemoptysis. Asthma occurs in 96-100% of patients.

• Upper respiratory tract: Symptoms commonly include allergic rhinitis, paranasal sinusitis, nasal polyposis.

• Cardiac: Cardiac involvement is relatively common, occurring in 62% of patients although only 26% are symptomatic. This includes myocarditis, restrictive cardiomyopathy, coronary artery disease, primary arrhythmias, acute constrictive pericarditis, and eosinophilic pericardial effusion.⁶ Cardiac involvement is more common in patients who are ANCA negative.

• Skin: Skin involvement is very common, affecting more than half of patients with EGPA. Purpura, skin nodules, livedo reticularis, urticaria, necrotic bullae, and digital ischaemia have all been described.

• Renal: Renal complications occur in 25% of patients with EGPA and includes glomerulonephritis and advanced chronic kidney disease. Hypertension is common, occurring in 10-30%, and may relate to renal involvement.

• Peripheral neuropathy: mononeuritis multiplex is the most frequent form. Less frequent symptoms include stroke and eye involvement.

• Gastrointestinal: Symptoms range from non-specific signs of pain, diarrhoea, and vomiting, to rarer manifestations including vasculitis and bleeding, bowel ischaemia and perforation, cholecystitis, and pancreatitis.

The third phase is characterised by the development of vasculitis, which tends to develop 3 to 9 years after the initial onset of asthma, and typically causes neurological symptoms.

• Neurological: This most commonly presents as mononeuritis multiplex or mixed sensorimotor peripheral neuropathy; wrist or foot drop is a common symptom. The most frequently affected nerves are the common peroneal and internal popliteal nerves, although the radial and ulnar nerves in the upper limbs can also be involved. Over 75% of patients develop a peripheral neuropathy; up to 39% of neurological manifestations involve a central nervous system vasculitis which can cause cerebrovascular accidents, both ischaemic and haemorrhagic.

Differential diagnosis¹

There are many possible differential diagnoses to consider but include:

• Other causes of systemic vasculitis:

  • Primary vasculitis - eg, polyarteritis nodosa, granulomatosis with polyangiitis.

  • Secondary vasculitis: a complication of a connective tissue disorder (eg, rheumatoid arthritis), infection, medication, or malignancy.

• Infections - eg, helminth/nematode.

• Idiopathic eosinophilic syndrome.

• Malignancy - eg, leukaemias, lymphomas, myeloproliferative neoplasms, solid cancers (especially gastrointestinal, breast or lung).

• Myelodysplastic syndromes.

Investigations¹

• Antineutrophil cytoplasmic antibodies (ANCAs): 30-40% of patients are perinuclear staining (p-ANCA) positive (antimyeloperoxidase antibodies).

• Other likely findings include:

  • Eosinophilia.

  • Normocytic normochromic anaemia.

  • Elevated ESR and CRP.

  • High IgE levels.

• Rheumatoid factor is positive in 60% of patients.

• CT scan of the chest often shows peripheral areas of parenchymal consolidation with ground-glass attenuation similar to chronic eosinophilic pneumonia, along with bronchial wall thickening. Pleural effusion occurs in 20-30% of patients.

• CT of the sinuses tends to show thickening of sinus mucosa.

• Lung function tests demonstrate an obstructive pattern in 70% of patients.

• A cardiac MRI scan is recommended in patients with EGPA, due to the poor prognosis associated with cardiac involvement, along with the frequency of such involvement being asymptomatic.

• Biopsies show evidence of disease. A skin biopsy tends to be the most straightforward to perform.

EGPA treatment and management⁷

The European Alliance of Associations for Rheumatology updated its treatment recommendations in 2024. ⁸ Under these guidelines EGPA treatment is considered separately from GPA treatment.

Treatment involves 2 stages: induction of remission, defined as the absence of active disease symptoms, and maintenance therapy.¹

• Corticosteroids are the first line treatment of choice. Remission is achieved in over 90% with corticosteroids alone, although relapses are common.

• Prednisolone at a dose of 1 mg/kg is normally sufficient although some patients with more severe disease require pulsed methylprednisolone.

• Mepolizumab is recommended for patients without severe or life-threatening complications but where there are frequent relapses.

• Cyclophosphamide is recommended for patients with severe or life-threatening complications. Retuximab is sometimes used as an alternative to cyclophosphamide. The Five Factor Score (see below) is used to determine the severity of disease.

Prognosis¹⁸

• Without treatment, the five-year survival rate is about 25%.

• However, patient outcomes have dramatically improved in recent years. With appropriate and timely treatment, the survival rate at five years is now 90% and ten-year-survival has been reported as 89%. ⁹

• Mortality rate has been reported to be close to that of the normal population and significantly better than the other ANCA-associated vasculitides,⁹although other studies suggest that there is still a significant mortality associated with EGPA.¹⁰

• Relapses is estimated as occurring in up to 30% of patients.

• The "Five Factor Score" is used to help determine prognosis with its features being associated with higher mortality.¹⁰ These five factors include:

  • Proteinuria (greater than 1 gm per day).

  • Renal insufficiency (Cr greater than 140 mmol/l).

  • Cardiac involvement.

  • GI tract involvement.

  • CNS involvement.

• More recent studies suggest that cardiac involvement has a better prognosis than previously thought, when patients are under specialist centres. It is postulated that this may be due to detection of milder cardiac pathology due to the use of cardiac MRI scans in asymptomatic patients or due to better awareness amongst physicians.⁸

• Complications of treatment are very common with a high prevalence of corticosteroid-induced adverse effects, including diabetes mellitus, myopathy, osteoporosis, vertebral fractures, and osteonecrosis of the femoral head. It is reported that nearly all patients with EGPA may develop long-lasting steroid-refractory neuralgia and myopathy.¹