Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)

Definition, Etiology, PathogenesisTop

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA) is a multisystem necrotizing granulomatous inflammation with eosinophilic infiltration of various tissues and organs. The lung is the most commonly involved organ, followed by the skin. EGPA can affect any other organ in the cardiovascular, gastrointestinal (GI), renal, and central nervous systems. In the respiratory tract, necrotizing inflammation affects predominantly small-sized and medium-sized vessels and is associated with concomitant asthma and eosinophilia. Nasal polyps as well as granulomatous and nongranulomatous extravascular inflammation (eg, nongranulomatous eosinophil-rich infiltrates of the lungs, myocardium, and GI tract) are often observed.

Clinical Features and Natural HistoryTop

1. Signs and symptoms:

1) General symptoms: Fever, weakness, anorexia, weight loss.

2) Respiratory manifestations: Asthma (in >95% of patients; usually severe), allergic rhinitis, often nasal polyps, acute or chronic sinusitis, pleural effusion, rarely hemoptysis due to alveolar bleeding.

3) Nervous system manifestations: Mononeuritis multiplex (in ~70% of patients), symmetric polyneuropathy (~60%), central nervous system symptoms (rare).

4) Renal manifestations: Glomerulonephritis (25%).

5) Cardiovascular manifestations: Eosinophilic endocarditis and/or myocarditis, vasculitis affecting coronary arteries (may lead to myocardial infarction), and pericarditis. Symptoms of heart failure and of secondary hypertension due to renal involvement.

6) Cutaneous manifestations (40%-70%): Palpable purpura. Less frequently subcutaneous nodules, urticaria, livedo reticularis, ulcerating papules.

7) GI manifestations: Eosinophilic gastroenteritis, intestinal ischemia, necrosis, and perforation due to vasculitis, manifesting as recurrent, often severe abdominal pain, diarrhea, and GI bleeding.

8) Other manifestations (rare): Obstructive uropathy (due to urethral narrowing or prostatic granulomas), myalgia, muscle weakness, arthralgia (usually without effusion), choroiditis.

2. Natural history:

1) Prodromal phase: In patients aged 20 to 40 years, allergic rhinitis is usually observed, sometimes with polyps and asthma (usually in patients >30 years).

2) Eosinophilia phase: Symptoms of eosinophilic infiltration of tissues, for instance, in the lungs and the GI tract.

3) Vasculitis phase: Usually within 3 years from the onset of symptoms (occasionally as late as after 30 years).

Vasculitis may resolve with time, while allergic symptoms may recur. The disease may also manifest with minor or atypical symptoms. The most frequent causes of death are cardiac complications (heart failure, myocardial infarction, cardiac arrest); less commonly, hemorrhage, renal failure, GI complications (perforation or hemorrhage), and respiratory failure.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests: Eosinophilia in peripheral blood (often >1.5×109/L or >10% of white blood cells), elevation in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, normocytic anemia, features of renal involvement (microscopic hematuria, proteinuria), a positive myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) test result (in ~60% of patients).

2. Imaging studies: Radiography and computed tomography (CT) reveal signs of chronic sinusitis and alveolar hemorrhage.

3. Pulmonary function tests: Features characteristic of asthma.

4. Histologic examination of samples of the involved organs (usually of the respiratory tract, skin, or kidneys): Patchy necrotizing vasculitis affecting small and medium vessels, necrotizing granulomatous inflammation with extensive eosinophilic infiltrates (nongranulomatous inflammation with eosinophilic infiltrates may also be present).

Classification Criteria

The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria should be applied to classify EGPA but only when a diagnosis of small-sized or medium-sized vasculitis has been made. Alternative diagnoses mimicking vasculitis should be excluded prior to applying the criteria (see Differential Diagnosis, below).

A score ≥6 is required for the diagnosis of EGPA.

1. Clinical criteria:

1) Obstructive airway disease (+3).

2) Nasal polyps (+3).

3) Mononeuritis multiplex (+1).

2. Laboratory and biopsy criteria:

1) Blood eosinophil count ≥1×109/L (+5).

2) Extravascular eosinophilic-predominant inflammation on biopsy (+2).

3) Cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) directed to proteinase 3 (PR3) (−3).

4) Hematuria (−1).

Differential Diagnosis

Differential diagnosis should include hypereosinophilic syndrome (HES), drug reactions (drug reaction with eosinophilia and systemic symptoms [DRESS]), parasitic or fungal infections, other systemic vasculitides, eosinophilic asthma/pneumonia, cancer, and lymphoma.

TreatmentTop

The choice of treatment depends on disease extent and prognosis and frequently requires a multidisciplinary approach (rheumatology, respirology, and hematology).

If symptoms are limited to mild asthma, allergic symptoms are present, or the patient is pregnant, glucocorticoid monotherapy can be considered.

For active nonsevere EGPA, glucocorticoids are typically used in conjunction with interleukin-5 (IL-5) inhibition (mepolizumab and, more recently, benralizumab), methotrexate, azathioprine, or mycophenolate for the glucocorticoid-sparing effect.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Wechsler ME, Akuthota P, Jayne et al; EGPA Mepolizumab Study Team. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. 2017 May 18;376(20):1921-1932. doi: 10.1056/NEJMoa1702079. PMID: 28514601; PMCID: PMC5548295. Guntur VP, Manka LA, Denson JL, et al. Benralizumab as a Steroid-Sparing Treatment Option in Eosinophilic Granulomatosis with Polyangiitis. J Allergy Clin Immunol Pract. 2021 Mar;9(3):1186-1193.e1. doi: 10.1016/j.jaip.2020.09.054. Epub 2020 Oct 14. PMID: 33065367. De Groot K, Rasmussen N, Bacon PA, et al.Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. doi: 10.1002/art.21142. PMID: 16052573. IL-5 inhibitor availability is often a limiting factor.

To decide on the treatment of severe disease, we consider the following 1996 Five-Factor Score (FFS), where the presence of 1 factor predicts a 5-year mortality rate of ~25% and the presence of 2 factors is associated with a 5-year mortality rate of almost 50%:

1) Proteinuria >1 g/d.

2) Renal insufficiency with serum creatinine >1.58 mg/dL (140 micromol/L).

3) GI tract involvement.

4) Cardiomyopathy.

5) Central nervous system involvement.

The presence of ≥1 factor indicates the need to add cyclophosphamide or rituximab, followed by maintenance therapy with methotrexate, azathioprine, or mycophenolate for the glucocorticoid-sparing effect, although it is often difficult to discontinue glucocorticoids completely.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). de Groot K, Adu D, Savage CO; EUVAS (European vasculitis study group). The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant. 2001 Oct;16(10):2018-27. doi: 10.1093/ndt/16.10.2018. PMID: 11572891. de Groot K, Harper L, Jayne DR, et al; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80. doi: 10.7326/0003-4819-150-10-200905190-00004. PMID: 19451574. Walters G, Willis NS, Craig JC. Interventions for renal vasculitis in adults. Cochrane Database Syst Rev. 2015 Sep 24;(9):CD003232. doi: 10.1002/14651858.CD003232.pub3. Update in: Cochrane Database Syst Rev. 2020 Jan 13;1:CD003232. PMID: 26400765. Harper L, Morgan MD, Walsh M, et al; EUVAS investigators. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis. 2012 Jun;71(6):955-60. doi: 10.1136/annrheumdis-2011-200477. Epub 2011 Nov 29. PMID: 22128076. Mohammad AJ, Hot A, Arndt F, et al. Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Ann Rheum Dis. 2016 Feb;75(2):396-401. doi: 10.1136/annrheumdis-2014-206095. Epub 2014 Dec 2. PMID: 25467294.
Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore). 1996 Jan;75(1):17-28. doi: 10.1097/00005792-199601000-00003. PMID: 8569467.