Better therapies for vasculitis: “avacoping” with the disease with less steroids

ANCA-associated vasculitis (AAV) is a systemic disease involving the formation of special autoantibodies (so-called anti-neutrophil cytoplasmic antibodies/ANCA) and vascular inflammation. There are several diseases associated with involvement of the kidneys, lungs, upper respiratory tract, heart, skin and the nervous system; potentially life-threatening courses of disease are also possible. Generally, this life-threatening disease includes three related forms of small-vessel vasculitis: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (or Churg-Strauss vasculitis).  Immunosuppressive therapy is provided, which can lead to infections as a known side effect, among others. Modern immunosuppressants (e.g. rituximab, an anti-CD20 monoclonal antibody) do not block the entire immune system as corticoids, for example, do, but only parts of it, so other pathways of the immune system continue to work. Indeed, although glucocorticoids have a relatively rapid onset of action, their use is associated with an overall negative impact on the patient’s health and health-related quality of life.

In the treatment of ANCA-associated vasculitis, these include increased risks of infection, diabetes mellitus, fractures, gastrointestinal bleeding, hypertension. Weight gain, sleep disturbance and neuropsychiatric disturbances (including irritability, anxiety, depression, and hyperactivity) have also been reported. A role in AAV pathogenesis is also played by the complement system of the immune system, especially complement factor C5a. The proinflammatory complement C5a ligand and its receptor C5aR (also referred to as CD88) appear to play a central role in the pathogenesis of ANCA-associated vasculitis. When stimulated by inflammatory cytokines, activation of the terminal C5a/C5aR axis generates an autoamplification loop that drives the acute necrotizing vasculitic process from primed neutrophils resulting from their interaction with ANCAs. Blood vessel distruction means that downstream tissue will suffer blood supply, and therefore oxygen, deprovation Avacopan is an orally selective C5aR antagonist that inhibits C5a-induced activation of immune cells and thus AAV – as already demonstrated in two clinical Phase II trials.

The phase III ADVOCATE trial evaluated the safety and efficacy of avacopan – also with regard to lower doses of glucocorticoids being needed with avacopan. Patients were randomized 1:1 and received, over a year, either the glucocorticoid prednisone (n=164) or avacopan (n=166) in combination with a) cyclophosphamide (oral or intravenous) followed by azathioprine or b) four infusions of rituximab (RTX). Patients were stratified on the basis of treatment (RTX or orally administered cyclophosphamide), the specific type of ANCA and newly diagnosed or relapsing AAV disease. Response to treatment (remission, primary endpoint) was defined as BVAS=0 (disease activity score) plus prednisone tapering (at least four weeks before week 26). Sustained remission was present if there was no relapse from week 26 to 52. At Week 26, 72% subjects achieved remission in the avacopan compared to 70% in the prednisone group. At week 52, 65.7% subjects achieved sustained remission in the avacopan compared to 54.9% in the prednisone group achieving both non-inferiority and superiority to prednisone group.

Professor David Jayne, explained and commented: “AAV must be treated with immunosuppressants. However, the side effects of these substances can be severe – especially at higher corticosteroid doses. With avacopan, a drug that could be available in the future a reduction in corticoid use and to more sustained remission is achieved – in the trial, at least 10% more patients were still in remission after one year. The benefit of avacopan in patients with renal involvement was remarkable and it was well-tolerated. Research is developing increasingly well-targeted immunosuppressive or immunomodulatory drugs for many areas of medicine. This is so important, because potentially life-threatening diseases such as AAV often require treatments that themselves pose risks – new immunosuppressive, specifically targeting substances are therefore urgently needed in order to improve therapies further and avoid the high dose steroids side effects”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical BIochemistry.

Scientific references

Lee A, Nissen MJ et al. Scand J Rheumatol. 2020 Jun 2:1-2.

Iudici M et al. Orphanet J Rare Dis. 2020 May 29; 15(1):130. 

Merkel PA et al. JMIR Res Protoc. 2020 Apr 7; 9(4):e16664.

Tesar V et al. Expert Opin Investig Drugs 2018; 27(5):491-96. 

Jayne DRW et al. J Am Soc Nephrol 2017; 28(9):2756-2767.

0 0 vote
Article Rating
Informazioni su Dott. Gianfrancesco Cormaci 2447 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it
Subscribe
Notificami

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.

0 Commenti
Inline Feedbacks
View all comments