Page 831 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 803

Because of the nature of AAV, relapse is common. Therefore Mycophenolate mofetil is a widely used transplantation drug
a single course of therapy rarely achieves long-lasting remission. that has been tested in AAV but is less effective than azathioprine
Repeat cycles of treatment are likely to be required, which accounts as maintenance agent for patients who have achieved remission.
for the accumulation of higher doses of cyclophosphamide, It is currently being tested against cyclophosphamide as an
especially in the pre-rituximab era. Therefore although each induction agent in AAV. Is typically given as 2–3 g/day as an oral
individual course of therapy may only contain 6–9 g, during a dose, along with reducing courses steroids. It is contraindicated
patient’s life time, they may require treatment for several relapses, in pregnancy.
which would then start building up the total exposure to cyclo- Cyclosporine is a well-established immunosuppressive drug
phosphamide. Nevertheless, even though it is being slowly that has been used for transplantation for many decades. Cyclo-
replaced, it remains an important aspect in the therapy of sporine has been given to limited numbers of patients with
82
vasculitis even in the present time. systemic vasculitis, with one small well-conducted trial in 32
Azathioprine is an immunomodulator with cytostatic proper- patients with GPA. In combination with plasmapheresis, it was as
ties. It inhibits cell division; it has been an effective immunosup- effective as continuous oral cyclophosphamide as a maintenance
pressant agent for decades. It was first used in combination with agent. It is generally limited by its toxicity and is not routinely
steroids and found to reduce mortality in systemic vasculitis in used.
82
an open-label retrospective study of 64 patients. The 5-year Leflunomide, an antilymphocyte agent used extensively for
survival of patients given no therapy was 12%, and those given the management of inflammatory arthritis, has been tested in
steroids alone had a 53% survival rate, whereas those treated patients with AAV in limited trials demonstrating its ability to
with steroids plus another agent (mainly azathioprine but a few maintain remission. Indeed, in a recent meta-analysis, it was
had cyclophosphamide) had a survival rate of 80%. It is an oral reported to be superior to azathioprine, MTX, and mycophenolate
medication given at 2–2.5 mg/kg/day, and it has largely been as a maintenance agent for AAV, but more trial data are needed.
superseded as an induction agent by cyclophosphamide. Aza- It is an oral agent that is characterized by a very long half-life,
thioprine is usually now used as maintenance therapy once the and it is not suitable for use in pregnancy.
disease has been controlled with another agent. It has been shown The role of hydroxychloroquine in mild forms of vasculitis
76
to be equivalent to methotrexate and superior to mycophenolate is uncertain. There is anecdotal evidence that it is beneficial in
as maintenance therapy. It is a relatively safe immunosuppressant patients with skin manifestations with small-vessel vasculitis. Its
and can be used safely throughout pregnancy. use probably stems from its known effects in the treatment of
Methotrexate (MTX) is popular among rheumatologists connective tissue diseases with skin and joint manifestations,
but less so among renal physicians who regard it with some such as SLE. Other similar agents, such as mepacrine and dapsone,
suspicion because of its potential for nephrotoxicity. The latter have also been used for skin vasculitis with occasional reported
is only the case for patients who have well-established renal positive outcomes. However, the potential toxicity for each of
disease (typically with a creatinine level >300 µmol/L). MTX is these agents should be considered alongside the relatively limited
an effective immunosuppressant agent used very widely in the evidence for benefit.
management of inflammatory arthritis and has found its place
in the management of GPA, where studies have demonstrated Specific Immunotherapy
78
its efficacy in comparison to oral cyclophosphamide. However, Better understanding of the pathogenesis of vasculitis (see section
it needs to be given continuously, rather than as induction on pathogenesis) has led to the development of targeted immu-
regimen over the short period of time. Although MTX is as notherapy for some of these diseases. Rituximab is an mAb against
effective as cyclophosphamide in inducing remission in GPA, B cells (Chapter 89) and has been in widespread use for treatment
stopping the drug inevitably leads to relapse. MTX is recom- of RA. Its role as an effective agent in AAV is well established
mended for non–life-threating AAV, usually in combination with with two randomized trials demonstrating efficacy comparable
78
steroid treatment. MTX is available either as oral, intramus- with cyclophosphamide. Rituximab induction therapy is just
cular, or subcutaneous administration. The dose is 20–25 mg/ as effective as cyclophosphamide for moderate and moderate-
week in most studies of vasculitis. It is contraindicated in to-severe AAV. Maintenance therapy with rituximab is a real
pregnancy. possibility with the potential to provide long-term control and
Cotrimoxazole, an antibiotic containing sulfonamide and trim- reduce relapse risk. The long-term consequences of repeat cycles
ethoprim, was fortuitously discovered to have beneficial effects in of rituximab, however, are unexplored. The risks are hypogam-
patients with GPA who had been treated coincidentally for infec- maglobulinemia, which occurs in most cases, and the potential
tions. There has been a significant advance in our understanding increase in incidence of infections. The most feared complication
of GPA, partly as a result of this historical experiment and partly is the risk of reactivation of the JC virus leading to the complica-
based on suggestions that S. aureus plays a role in initiating disease tion of progressive multifocal leukoencephalopathy (PML), which
by its effect on the nasal mucosa. Eradication of the organism has has a very high mortality rate.
been suggested as one mechanism by which it works, although
the drug is not particularly effective against this organism. It is Other Therapies
more likely that the drug has an immunosuppressive effect in Belimumab is currently undergoing clinical trials as a maintenance
itself; it has been demonstrated to be effective in combination agent for AAV. The drug is a BAFF inhibitor and may be an
with low-dose steroids in a randomized trial of localized forms of effective means to control the disease over the long term.
78
GPA. It is also commonly used as a prophylactic agent against Mepolizumab is an mAb directed against IL-5, which controls
Pneumocystis jiroveci infection; it is given 3 times per week for eosinophil production. Mepolizumab has been successfully used
patients receiving other more potent immunosuppressant therapy, in the treatment of hypereosinophilic syndrome and is undergoing
such as cyclophosphamide or even MTX (despite the potential a trial in EGPA. IVIG (Chapter 84) has been available as a
for drug interactions leading to anemia). replacement therapy for patients with hypogammaglobulinemia