Page 617 - Clinical Immunology_ Principles and Practice ( PDFDrive )

594 ParT fivE Allergic Diseases

Second-Line Therapy involved in the breakdown of bradykinin. Angiotensin II recep-
It has become common practice to increase second-generation tor agonist (ARA 2) are probably safe alternatives. Exogenous
antihistamines above their licensed doses up to fourfold when estrogen (oral contraceptives and hormone replacement therapies)
CU does not respond because clinical experience and updosing should be avoided in women, since it appears to activate kallikrein
studies show that this achieves better control in some patients. through activated factor XII. Lifestyle events that exacerbate HAE
When urticaria does not respond to first-line measures, systemic vary in their importance among individuals but may include local
corticosteroids are commonly used as short-term rescue therapy trauma (e.g., dental extraction), stress, tiredness, and intercurrent
for acute urticaria or severe exacerbations of CU. Long-term infections, possibly including Helicobacter pylori infection. Attacks
treatment with oral corticosteroids is not recommended because involving the extremities or abdomen are the most common. It is
of safety concerns. In corticosteroid-dependent patients, an estimated that over their lives, up to 50% of patients will experi-
alternate-day dosing schedule may be used, and steroid-sparing ence an attack of oropharyngeal swelling, with risk of asphyxiation,
drugs should also be considered. A wide variety of medications so treatment must be rapidly available for emergencies in all
have been reported to be of benefit for antihistamine-unresponsive patients as well as as a preventive measure. The intention of
urticaria when oral corticosteroids might otherwise have to be treatment is to reduce or curtail the severity of a swelling and to
considered, but they are invariably used off-label, and controlled reduce “downtime” if one occurs. Some patients with frequent
trials are usually lacking. Where possible, these should be targeted peripheral swellings prefer to treat themselves symptomatically
at specific subgroups of urticaria patients (e.g., the LT receptor with analgesics and wait for spontaneous resolution over 3–4
antagonist montelukast has been shown to be effective in aspirin- days, rather than have specific treatment, since no treatment is
sensitive patients with CSU, and there is limited evidence for a completely without risk of adverse effects, and there are potential
trial of thyroxine in biochemically euthyroid patients with CSU problems with cost and/or availability. The management of types
who have thyroid autoimmunity). I and II HAE is better defined than type III but follows similar
principles. 24
Third-Line Therapy
The recent approval of omalizumab (anti-IgE) as add-on therapy Treatment of the Acute Attack
for CSU not responding to antihistamines has transformed the The “gold standard” treatment for oropharyngeal or GI attacks
management of severe disease in many patients. The recom- in most countries (except the United States until recently) has
mended dose is 300 mg by monthly subcutaneous injection, been plasma-derived nanofiltered C1 esterase inhibitor (pd-
although clinical experience indicates that lower (and occasionally C1-INH) concentrate given by intravenous infusion. It has proven
higher) doses may be effective and the interval between treatments to be effective and safe. The recommended dose is 20 units/kg
can be extended in good responders. Clinical experience suggests body weight in adults and children, although smaller doses have
that when used off-label, it may also be effective for many patients been used in the past and may be effective. Up to 3 units of fresh
with inducible urticarias. The mechanism of action is still not frozen plasma (containing C1 inhibitor and its substrate, comple-
certain but probably involves reduction of high-affinity IgE ment) may be given as an alternative in an emergency when
receptors on mast cells and basophils as a consequence of a rapid pd-C1-INH is not available, but it will not have had the same
fall in circulating free IgE and a later reduction in IgE bound to stringent screening and production measures to eliminate the
mast cells, resulting in a stabilizing effect. Experience to date possibility of transmissible infection. Initial improvement in the
suggests that omalizumab is often highly effective for control of swelling may be seen within 30–60 minutes, and time to clearance
urticaria symptoms (including itch) but probably does not modify is usually in the order of 24 hours after pd-C1-INH. Self-
the natural history of the illness. administration can reduce the severity of attacks by allowing
Immunosuppressive therapy is mainly considered for auto- earliest treatment and should be encouraged. A recombinant
immune CSU. However, it may also benefit therapy-resistant C1-INH is licensed in Europe. Icatibant (a bradykinin 2 receptor
CSU without evidence of circulating antibodies. antagonist) is also highly effective for acute episodes of HAE.
The best-studied immunosuppressive therapy is cyclosporine, Ecallantide (a kallikrein antagonist) is currently licensed in the
shown to be effective initially at 4 mg/kg daily in patients with United States but not in Europe. Both are given by subcutaneous
CSU. Patients must be monitored carefully for renal impairment injection, which provides an easier route for administration than
and hypertension; treatment should normally be limited to 4 intravenous infusion. Ecallantide should be given under medical
months. Cyclosporine is contraindicated in patients with previous supervision, since there is a small risk of allergic reactions.
malignant disease except nonmelanoma skin cancer. There is Icatibant is licensed for self-administration, which provides a
some evidence for efficacy of plasmapheresis and immunoglobu- potential advantage. There have been no head-to-head studies
lins in chronic autoimmune urticaria, although these are expensive of pd-C1-INH, ecallantide, and icatibant, but experience suggests
options, and controlled clinical trials are needed. Methotrexate, that the effectiveness of these products is comparable. It should
mycophenolate mofetil, and azathioprine have also been used be noted that antihistamines and steroids have no place in the
alone or with corticosteroids. 14 management of HAE. Any improvement resulting from epineph-
rine’s effects on vasopermeability will be transient, and there is
MANAGEMENT OF HEREDITARY ANGIOEDEMA no evidence that it changes the overall course of an attack.
The swellings of HAE are mediated by kinins rather than hista- Short-Term Prophylaxis
mine, so the management of HAE is completely different from It has become common practice to give prophylactic treatment
mast cell–dependent urticaria. The primary aim of therapy is to with pd-C1-INH before procedures involving local trauma to the
replace the missing functional C1 esterase inhibitor or stabilize oropharynx, including dental extraction and intubation for general
the coagulation, fibrinolysis, complement, and kallikrein–kinin anesthesia. The dose for prophylaxis may be less than that needed
pathways. ACEIs should be avoided because ACE is a key enzyme for treatment of an acute attack. Common practice is to give at