Een internationale gerandomiseerde open label studie waarbij een op rituximab gebaseerde de behandeling vergeleken wordt met hun standaard behandeling met cyclofosfamide/azathioprine bij de behandeling van patienten met actieve gegeneraliseerde ANCA geassocieerde vasculitis

The ANCA associated vasculitides (AASV), namely Wegener*s granulomatosis,
microscopic polyangiitis, and renal limited vasculitis are autoimmune,
multi-system,
progressive diseases which untreated can lead to rapidly progressive renal
failure and death.
Randomised, prospective, clinical trials have demonstrated the efficacy of
immunosuppressive treatments for vasculitis and have defined treatment
protocols at different disease points. The current *gold standard* treatment
for active AASV with glomerulonephritis is cyclophosphamide with steroids.
However the standard treatment is associated with significant morbidity and
mortality, largely due to infections and malignancy with cumulative
cyclophosphamide dosing. Other effective treatments for AASV are being sought,
with safer side effect profiles. Rituximab is an anti CD20 chimeric monoclonal
antibody, which is used for the treatment of non-Hodgkin*s lymphoma (NHL). It
is well tolerated in humans with a good safety profile. Rituximab has been
shown in small series to induce remission in AASV and is now being increasingly
used for other (non-ANCA) autoimmune conditions such as lupus and rheumatoid
arthritis.
RITUXVAS has been designed to test the hypothesis that Rituximab leads to a
higher rate of sustained remission compared to standard therapies
(cyclophosphamide /azathioprine) with a lower rate of adverse events and
reduced cyclophosphamide exposure as treatments for active, *generalised* AASV.
We plan a randomised phase II/phase III trial to compare a rituximab based
regimen to standard of care. For the initial phase II part, 44 patients will be
randomised 3:1 to rituximab or control. Following this analysis, the trial may
be extended to a phase III stage. The trial will be conducted by 14 centres
from 8 countries.

Betere behandeling

International, randomised, controlled, prospective, open tril comparing a
rituxmab based regimen with a standard cycloshosphamide/azathioprine regimen in
the treatment of active 'generalised' AASV.

Rituximab Rituximab is an anti CD 20 chimeric mouse/human monoclonal antibody, with human IgG1 constant regions and murine light/heavy chain variable regions (7). CD 20 is a ligand which exists on developing B cells, excluding stem cells and plasma cells. The role of the CD 20 ligand in nature is not fully understood, although mediation of apoptosis has been suggested. The mechanisms by which rituximab causes B cell depletion may involve complement induced B cell lysis, Fc receptor mediated cytotoxic cell killing or the direct induction of B cell apoptosis by rituximab. Rituximab therapy correlates positively with B cell depletion and rituximab levels. Different dosing regimens have been trialled. In patients with systemic lupus erythematosus (SLE), the efficacy of rituximab is dependant upon B cell depletion. 4 infusions of 375mg/m2 rituximab infusions (one per week for four weeks) were required for this to occur (13,14). In 3 published reports 375mg/m2 has resulted in B cell depletion and clinical response in patients with refractory vasculitis (10-13). On the basis of these results a dose of 4 x 375mg/m2 infusions will be used in RITUXVAS. In RITUXVAS, 2 doses cyclophosphamide will still be administered with the 1st and 3rd rituximab infusions, for two reasons. Firstly, the necrotising cresentic glomerulonephritis associated with AASV progresses rapidly and the therapeutic effect of rituximab is delayed. The use of cyclophosphamide/high dose steroid, which are standard components of induction therapy, will allow adequate immunosuppression in the early crucial treatment of AASV. Secondly, human anti-chimeric antibody (HACA) formation has been reported in NHL, SLE, and RA with varying frequencies, (4.3% of patients in RA (8)). The long term implications of these antibodies are not known. However, the possibility of anaphylactic reactions and rituximab resistance with further treatments exists. Co-administration of an immunosuppressant effective in the treatment of vasculitis is thus a logical approach to minimise HACA development. Rituximab has now been used to treat 300,000 patients with NHL. Long-term safety regarding carcinogenicity and fertility has yet to be established. However, no major long-term adverse sequelae have been reported (1). Up to 50% of patients receiving rituximab for an indication will develop infusion reactions with symptoms including; fevers, chills, rigors, flushing, throat irritation rash rhinitis fatigue headache, nausea, vomiting, urticaria, angioedema, bronchospasm, myalgia, arthralgia, hypotension, hypertension and exacerbation of angina or congestive cardiac failure. Later reactions include diarrhoea, leucopenia, neutropenia, thrombocytopenia, anaemia, and infections in 30%, which may or may not be drug related (investigators brochure).

In de huidige studie wordt de standaard behandeling met cyclofosfamide en
prednison vergeleken met een cyclofosfamide sparende behandeling met rituximab
prednisolon en cyclofosfamide. Het risico op bijwerkingen van rituximab moet
worden afgezet tegen het risico van bijwerkingen op cyclofosfamide. Een
belangrijke bijwerking van rituximab is de formatie van anti stoffen tegen
rituximab (HACA). Een enkele keer wordt de antistof formatie tegen rituximab
gecompliceerd door serumziekte. Dit zal wellicht in de huidige studie voorkomen
kunnen worden door dat de patiënt behalve rituximab ook prednisolon en Endoxan
krijgt. Hierdoor wordt de HACA formatie sterk geremd. Daarnaast kunnen
infusiereacties optreden bij rituximab. Over het algemeen zijn dit niet
ernstige passagere reacties. Late reacties zijn infecties en hematologische
afwijkingen. Deze zullen zeker niet ernstiger zijn dan die bij de standaard
therapie optreden. Indien de behandeling met rituximab even effectief is of
standaardtherapie is het te verwachten dat er minder bijwerkingen optreden bij
de rituximab therapie in vergelijking met de standaardtherapie.