During the past decades there has been an increased interest in the small vessel vasculitides, such as granulomatosis with polyangiitis (GPA, “Wegener’s granulomatosis”) and microscopic polyangiitis (MPA), both associated with circulating anti-neutrophil cytoplasmic antibodies (ANCA). Thus, these diseases are often referred to as “ANCA-associated vasculitis” (AAV).
The first step towards better outcome was taken by the introduction of corticosteroid and cyclophosphamide for induction of remission of GPA, presented by Fauci and Wolff in 1973, resulting in a dramatic improvement of patient survival from 10% in un-treated patients to 80% at 2-years of follow-up. However, the side-effects of the “Fauci-regimen” were frequent and serious and relapse rate was high, above 50%.
EUVAS; European Vasculitis Study Group, was established in 1993 as a development of the previous work from the European group standardizing ANCA-serology. Several randomized clinical trials (RCT) have been conducted within EUVAS and so far, the results from six RCT have been published. One of EUVAS’ first studies “CYCAZAREM” revealed that remission sustaining therapy with azathioprine was as good as cyclophosphamide preventing relapses.
During the last decade treatment regimens have focused on decreasing the burden of immunosuppression in an attempt of reducing toxicity and severe side-effects such as infections. New therapies have come into the field, such as anti-CD20 (rituximab) and deoxyspergualin. Rituximab has been found to be an alternative as induction of remission of the severe cases of AAV.
Within EUVAS we have recently, with support from EULAR, published several reports on the long term follow-up of a cohort comprising 535 patients participating in the EUVAS’ first four RCTs, followed-up for 5 years. This cohort comprised 281 patients with GPA and 254 with MPA, 46% were females, 53% had PR3-ANCA, and median age at inclusion of RCT was 61 years. The majority, 65%, had an estimated glomerular filtration rate >15 ml/min. and the median value of BVAS was 17.
The patient survival at 2 and 5 years was 85% and 78%, respectively. The overall mortality ratio was significantly higher, 2.6 (95% CI 2.2-3.1), than the calculated survival from an age- and sex-matched general population. The risk of death was highest in the first year of follow-up; mainly due to either infection or active vasculitis. After one year of follow-up the causes of death was attributed to infection, cardiovascular event or malignancy. Significant predictors for mortality were old age, renal insufficiency i.e. glomerular filtration rate <15ml/min., and higher BVAS.
Cardiovascular events are common in the AAV-population, 14% of patients having at least one cardiovascular event within 5 year of follow-up, older age was associated with a higher risk, while PR3-ANCA was associated with a lower risk vs. MPO-ANCA.
Previous publications have revealed an increased risk of malignancy during follow-up. However, the results from EUVAS’ five year follow-up could not support this, with the exception of non-melanoma skin cancers. This could be explained by a lower cumulative dose of cyclophosphamide, or to a limited follow-up period (5 years).
Five-year follow-up of patients in the four clinical trials respectively have shown some interesting results, demanding further long-term follow-up and analyses. For the CYCLOPS trial, the 5-year follow-up revealed that for patients with PR3-ANCA continuous oral cyclophosphamide was associated with fewer relapses compared to the intermittent pulse regimen.
Thus, we still have to improve the therapy, continuously searching for a cure. However, this is not possible until the pathogenesis of the vasculitides has been revealed. Until then, we have to extend the follow-up of the randomized controlled trials, as there seems to be some results that have to wait for detection.
Disclosure of Interest None Declared