Supplement Article |
OP26. THERAPY IN VASCULITIS
Addenbrooke's Hospital, Cambridge, UK
The treatment of vasculitis has developed empirically with the introduction of corticosteroids and their subsequent combination with immune suppressive drugs, especially cyclophosphamide. Over the last fifteen years, prospective multi-centre studies have helped determine optimum drug regimens and have attempted to design regimens according to disease extent and severity. Common features of these trials have been the high rates of treatment toxicity reported and the risk of disease relapse when treatment is reduced or withdrawn. These are the two principal targets for newer therapeutics. Furthermore, current regimens are not necessarily effective at restoring the patient to their pre-morbid state of health and the apparent disease remission seen by physicians is not reflected in normalisation of quality of life. Subclinical disease activity may persist, although this is difficult to study without improved biomarkers of disease. Current studies are exploring alternative immune suppressives, such as mycophenolate mofetil and deoxyspergualin, and the optimal duration of therapy.
Two newer therapeutic approaches have taken advantage of recombinant antibody technology and drugs developed for more common, and profitable, indications. Lymphocyte depletion aims to remove autoreactive lymphocytes and thereby control disease. Anti-thymocyte globulin and anti-CD52 (CAMPATH-1H) have had the effect of depleting T cells and both strategies have been effective in vasculitis. This confirms a T cell role in the pathogenesis of vasculitis but these drugs are associated with high levels of intercurrent infection and have never entered routine use. B cell depletion with Rituximab has been surprisingly effective in autoimmunity and has emphasised a role for B cells in supporting autoreactive T cell activity. Several studies in ANCA associated vasculitis have reported high rates of success and other vasculitides are now being studied. B cell depletion appears to be safe and to lead to prolonged remission, re-treatment seems to be uncomplicated and effective. The other strategy has been cytokine depletion especially with agents blocking tumor necrosis factor (TNF). Results in small vessel vasculitis have been conflicting with short term studies suggesting benefit and larger, longer term studies not finding any sustained effect. Uncontrolled studies in giant cell arteritis and Takayasu's disease have been promising and it will take some time to clarify the optimal indications, therapeutic agent dose and duration of therapy for TNF blockade in vasculitis.
With the development of large clinical trial databases during the 1990s longer term follow-up studies are now feasible in vasculitis. Preliminary results have revealed increased mortality and increased cardiovascular risk but there is no clear indication of an increase in malignancy. It will be important to determine how current therapeutic strategies influence longer term outcomes and whether additional interventions are required to reduce these increased risks.