Eosinophilic Granulomatosis With Polyangiitis Cohort

Background Eosinophilic Granulomatosis with Polyangiitis (EGPA, previously Churg-Strauss Syndrome) is a rare, idiopathic, ANCA associated vasculitis (AAV), alongside Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA). It is an eosinophilic small/medium vessel vasculitis characterised by asthma, rhinosinusitis and eosinophilia. Patients can also suffer renal, cardiac, gastrointestinal and neurological involvement. First described by Churg and Strauss in 1951, exact epidemiology remains difficult because of a lack of clear diagnostic criteria. It appears to have a prevalence of around 11-13 per million population with a mean age of 50 years old and represents 10% of diagnosed vasculitides.

Following Churg and Strauss' original paper, the first attempt to provide diagnostic clarity was provided by John Lanham in 1984. Lanham listed symptoms seen in a set of patients with EGPA and suggested which symptoms were required for the disease and which symptoms were "additional". The American College of Rheumatology (ACR) in 1990 published a list of 6 symptoms to assist with classification of vasculitides, created by comparing 20 patients with EGPA with 787 patients with other forms of vasculitis. This was frequently used for diagnosis despite being intended for classification. In 1994, and revised in 2012, the International Chapel Hill Consensus Conference produced a nomenclature and definition for vasculitides, again frequently incorrectly used as diagnostic criteria. Finally, in 2014, diagnostic criteria were provided by the European Respiratory Society Churg Strauss Syndrome (ERS-CSS) taskforce; however published literature still uses a variety of criteria.

EGPA is recognised as a Th2 predominant disease with elevated levels of IL-4, IL-5, IL-13 and IgE according to a number of case control studies and case reports. Association between IL-10 levels and ANCA negative EGPA has been reported. Th17 responses also seem to be elevated with raised serum IL-25 reported, potentiating Th2 cytokine release. Eosinophil products are detectable in serum, BAL, urine and biopsies with varying time-courses. Roles of other cells such as regulatory T cells, memory T cells, dendritic cells, macrophages, ILCs and others are being investigated.

Previous work within the investigators' unit has demonstrated disturbances in the coagulation system in patients with asthma. The investigators have demonstrated that, while moderate asthma appears to favour fibrinolysis, severe asthma is a fibrinogenic condition. Deposition of fibrin within the airways in fatal asthma has been previously recognised, but a case study demonstrated strong activation of the coagulation system five days prior to an exacerbation. Another case study has demonstrated increased activation of the coagulation system in a patient with active EGPA which normalised on remission, but more in depth work has not been done.

It has been previously recognised that ANCA positive patients often have a different disease phenotype to those who are ANCA negative, suffering with more vasculitic symptoms and renal disease but less cardiac involvement. In 2014 the ERS-CSS taskforce provided diagnostic criteria for these two main phenotypes - separating the vasculitic phenotype which remains called Eosinophilic Granulomatosis with Polyangiitis (EGPA), from the ANCA negative tissular phenotype called Hypereosinophilic Asthma with Systemic Manifestations (HASM). It is currently unclear if this distinction matches biological endotypes, or whether different treatment strategies are advisable between the two groups. It is possible that HASM is a precursor state to full vasculitic EGPA, however the increased incidence of cardiac manifestations within this group would point away from this, as would the differing prevalence of genetic markers such as IL-10 promoter activation.

Prior to the advent of corticosteroid use, prognosis of EGPA was poor with a mortality rate of 50% at 3 months. Treatment primarily consists of immunosuppression with corticosteroids, with induction therapy using cyclophosphamide in severe cases. Rituximab is approved for use in GPA and MPA, while case reports demonstrate a good effect in patients with severe, refractory EGPA, uncontrolled on other therapy. Those who suffer from CSS can be exposed to prolonged steroid therapy with the majority of patients experiencing side effects of their medication such as weight gain, osteopaenia, impaired glucose tolerance, cataracts and skin atrophy. Steroid sparing agents such as azathioprine and mycophenolate are used with variable effect. Treatment is primarily guided by eosinophil count and symptom scores such as the Birmingham Vasculitis Activity Score (BVAS) as there are not currently any diagnostic tests or EGPA-specific biomarkers. Presence of a specific biomarker would allow more accurate alterations in patients' mediation, as non-specific symptoms can imitate EGPA and prompt increases in steroid doses.

Research questions Do the ERS-CSS diagnostic criteria divide the PHT cohort into groups with distinct clinical characteristics? How do the EGPA and HASM groups differ in clinical and physiological characteristics and how do these change over time?

Potential impact If the investigators confirm that EGPA and HASM represent distinct clinical entities within our cohort, further research into biological mechanisms and treatment options is needed, and this work will help to guide further studies.