Page 830 - Clinical Immunology_ Principles and Practice ( PDFDrive )

802 Part SIX Systemic Immune Diseases

study demonstrated the superiority of plasmapheresis over IV
No Treatment/Symptom Relief prednisolone, both used as adjunct therapies (in combination with
Small-vessel vasculitis, such as isolated cutaneous vasculitis cyclophosphamide and high doses of oral prednisolone) for treat-
resulting from infection or use of pharmaceutical agents, may ment of severe AAV (mainly MPA plus some cases of GPA) with
respond to simple withdrawal of the offending agent or resolution significant renal impairment (creatinine levels above 500 µmol/ L
of the infection without the need for specific treatment. However, [5.66 mg/dL]).
for more recalcitrant disease, symptom relief may be required The role of glucocorticoid therapy is been increasingly chal-
and occasionally systemic steroids. Symptom relief could be lenged by more recent trials using smaller doses for shorter
provided in the form of antipruritic agents or topical cream to periods or even eliminating steroid use completely in some
reduce skin inflammation and/or topical steroids. NSAIDs can instances. Glucocorticoid side effects are well known: weight
be helpful in relieving symptoms of joint pain or swelling. As loss, increased appetite, mood swings, hypertension, risk of
monotherapy they are unlikely to resolve skin manifestations diabetes, risk of infection, risk of cataract, and skin striae. The
but could be tried in combination with other therapies. Colchicine risk of osteoporosis is largely preventable with concurrent use
has been used for skin vasculitis and occasionally can be effective, of bisphosphonate therapy (unless there is significant renal
although the doses required should remain below 2 mg/day to dysfunction) with supplementary calcium and vitamin D
avoid the predictable side effects of abdominal cramps and replacement.
diarrhea.
Other Immunosuppressive Therapies
Target-Directed Therapies Cyclophosphamide (Chapter 87) has been available since the
In diseases where there is a clearly defined provoking agent, as 1950s but was first used for the management of systemic vasculitis
in hepatitis B–related PAN or hepatitis C–related cryoglobulinemic in the 1970s and remains the most effective agent we have for
vasculitis, eradication of the virus is a key part of treatment of managing multiorgan systemic vasculitis. Initially it was used as
the disease. Effective antiviral agents play a vital role in the a daily oral agent at 2–3 mg/day, and it transformed the outcome
management of virus, associated with the need for immunosup- of patients with AAV from inevitable mortality to a high likelihood
pression. Hepatitis B–related PAN is treated with a combination of survival. It is a cytotoxic agent and carries with it the risk
of antiviral therapy plus plasma exchange to remove immune- associated with chemotherapy, including increased risk of
complexes and other inflammatory mediators combined with a malignancy, especially in the bladder because it is predominantly
course of glucocorticoid therapy. For hepatitis C–related cryo- excreted through the kidneys and accumulates in the bladder.
globulinemic vasculitis, recent reports of virus eradication may Initial protocols were associated with excessive risks of bladder
also be transforming the outcome of this disease. Unfortunately, cancer (approximately 33-fold), but despite this, the daily oral
the toxicity of these regimens can be considerable, with >40% cyclophosphamide dosing regimen was not effective in maintain-
requiring erythropoietin, red blood cell transfusions, and or ing control of disease. Therefore over the past 20 years or so,
G-CSF. there have been a number of trials comparing reduced doses of
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cyclophosphamide, high-dose intermittent pulse therapy, or
Specific Therapies with combination strategies of induction with short courses of
In KD, although the etiological factors have not yet been defined, cyclophosphamide followed by a switch to another drug for
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it seems likely that this is related to some kind of infectious maintenance, or by replacing cyclophosphamide with another
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agent (see earlier section on pathogenesis). The most effective agent, such as methotrexate. All these studies have demonstrated
therapy is use of high doses of IVIG (0.4 g/kg/day for 5 days) the equivalence of using shorter courses of daily oral cyclophos-
combined with high doses of aspirin, which is usually curative. phamide and, more recently, of using of high-dose intermittent
Whether or not this will prevent long-term harm to the cardio- pulses of cyclophosphamide to reduce the total dose even further.
vascular system, particularly the coronary arteries, remains to The total cumulative dose from six cycles of cyclophosphamide
be explored. over a period of 3 months would be 6 g (based on 15 mg/kg/
treatment on six occasions). This compares with 9–12 g of
Glucocorticoids cyclophosphamide given as daily oral therapy over 4–6 months. 81
Glucocorticoids (Chapter 86) remain a cornerstone in the Although the relapse rate for patients given high-dose intermit-
management of most forms of multisystem vasculitis. They are tent cyclophosphamide was higher during the subsequent 5 years
relatively contraindicated in KD because they may potentially compared with that for patients who were not given daily oral
worsen the development of coronary artery aneurysm, but cyclophosphamide, relapse was always effectively managed with
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they have been used in combination with IVIG and aspirin reintroduction of therapy and never led to mortality. The
with beneficial outcomes. However, they are an integral part of consequences of exposure to cyclophosphamide are likely to be
almost all therapeutic regimens for management of vasculitis. risk of cancer (more recent studies suggest that this risk is relatively
In some instances, such as isolated skin vasculitis, they are the modest now that the regimens include much lower total doses),
only treatment required, but more often they are insufficient infertility, hair loss, nausea, vomiting, diarrhea, cytopenia, and
on their own without causing significant morbidity from side increased risk of infection. Less common complications of
effects. Typical doses of glucocorticoid therapy are 1 mg/kg/ cyclophosphamide include hyponatremia. The introduction of
day over a period of 2–4 weeks, reducing to around 10–15 mg/ rituximab for AAV has had a significant impact on the use
day within 6 months, and then slowly withdrawing steroids of cyclophosphamide, with increasing numbers of patients being
in the next 6–12 months. The use of high-dose intravenous managed with rituximab in place of cyclophosphamide, especially
methylprednisolone is popular but lacks evidence. The only if patients are of child-bearing years, or if there is a potential
randomized trial of intravenous methylprednisolone compared contraindication to using cyclophosphamide, such as a previous
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it against plasma exchange in patients with severe AAV. This history of bladder cancer.