Page 860 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 60 Systemic Autoinflammatory Syndromes 831

TABLE 60.5 Diagnostic Criteria for As colchicine is the only drug with proven protection against
Periodic Fever, aphthous Stomatitis, the development of amyloidosis, all patients with FMF should
Pharyngitis, and adenitis (PFaPa) Syndrome be prescribed colchicine, regardless of disease severity and attack
frequency. When anti–IL-1 treatment is started, expert opinion
I Regularly recurring fevers with an early age of onset (<5 years of recommends continuation of colchicine in the highest tolerable
age) dose for the prevention of amyloidosis.
II Constitutional symptoms in the absence of upper respiratory The most common side effects of colchicine are diarrhea
infection, which include at least one of the following:
a) Aphthous stomatitis and abdominal pain. These are dose dependent. In patients with
b) Cervical lymphadenitis persistent diarrhea, dose reduction can be tried to reduce severity.
c) Pharyngitis Myopathy, neuropathy, and leukopenia are very rare, but severe
III Exclusion of cyclic neutropenia side effects occur primarily in patients with abnormal kidney
IV Completely asymptomatic interval between episodes or liver function or because of interaction with other drugs.
V Normal growth and development
High-dose colchicine has been shown to be teratogenic in
From: Thomas et al. Diagnostic criteria used for PFAPA Periodic fever syndrome in animals. However, multiple cohort studies have shown that
children. J Pediatr 1999;135:15–21 colchicine can be used safely during pregnancy and breastfeeding.
In therapeutic doses, colchicine does not have a negative effect
on sperm number and quality, and it has no negative effect on
male or female fertility.
As a general rule, there is no place for colchicine in the treat-
Periodic Fever, Aphthous Stomatitis, Pharyngitis, ment of autoinflammatory syndromes other than FMF. As an
and Adenitis Syndrome exception to this rule, patients with autoinflammation of unknown
There is currently no diagnostic test to prove PFAPA. It is origin may experience a favorable effect, especially if their disease
diagnosed based on clinical signs and symptoms. The modified shares characteristics with FMF. A small trial has demonstrated
criteria by Thomas et al. are used (Table 60.5) and may be supple- decreased attack frequency during colchicine treatment for
mented by numeric limits, such as minimum number of attacks PFAPA. 23
and duration of fever. Exclusion of other causes, including other
autoinflammatory syndromes, is important. Inhibition of Interleukin-1
Schnitzler Syndrome KEY CONCEPTS
Schnitzler syndrome is diagnosed on the basis of clinical criteria Interleukin-1β (IL-1β)
(see Table 60.2). Exclusion of other causes, particularly mono-
clonal gammopathy of undetermined significance (MGUS) and • IL-1β is a very potent proinflammatory cytokine, tightly regulated at
chronic idiopathic urticaria, is of paramount importance. multiple levels.
• The majority of autoinflammatory diseases is caused by dysregulation
Autoinflammation of Unknown Origin of IL-1β.
• Measurement of IL-1 β serum levels has no value in the diagnosis of
Regardless of the increasing number of autoinflammatory diseases autoinflammation or in assessing disease severity.
recognized and the increasing insights in the mechanisms of • IL-1 inhibition is the treatment of first choice for many autoinflammatory
autoinflammation, an increasing number of patients presenting diseases, and it has greatly improved quality of life in patients.
with an autoinflammatory phenotype cannot be assigned to
one of the known autoinflammatory diseases. These patients
are considered to suffer from autoinflammation of unknown
origin. It is likely that further research and newly developed
diagnostic techniques will identify new proteins, genetic defects, The detection of NLRP3 mutations in CAPS has illustrated the
and pathways in these patients, leading to recognition of new importance of IL-1β in the pathogenesis of autoinflammation.
diseases. In patients with autoinflammation of unknown The first inhibitor of IL-1 developed was the recombinant
origin, anti–IL-1 therapy can be tried both diagnostically and human IL-1 receptor antagonist anakinra, which is still the most
therapeutically. 21a commonly available IL-1 inhibitor. It competitively binds to the
IL-1 receptor, completely inhibiting the actions of both IL-1α
TREATMENT and IL-1β. Anakinra has a short half-life and needs to be given
as a once-daily subcutaneous injection.
Colchicine The selective anti-IL-1β monoclonal antibody canakinumab
Colchicine is the treatment of first choice for FMF. Although it has a longer half-life and is also injected subcutaneously. Standard
has been used since the 1970s, the mechanism of action of injection frequency is once per 8 weeks, but shorter intervals
colchicine in FMF is still unknown. It is highly effective in prevent- may often be necessary in severe disease.
ing attacks. Response to colchicine has been used as a diagnostic Rilonacept is a construct of two extracellular chains of the
criterion for FMF. IL-1 receptor complex fused to the Fc-portion of IgG. It is given
The average dose used is 1.0–1.5 mg/day. If tolerated, the as a weekly subcutaneous injection.
dose can be increased up to 3 mg/day in patients with insufficient Currently, there is evidence for the effectiveness of anti–IL-1
response. There are few patients with FMF that are unresponsive therapy in many autoinflammatory diseases, including FMF,
to colchicine. Others may not be able to tolerate an effective CAPS, TRAPS, MKD, PFAPA, and Schnitzler syndrome. Typically,
dose of colchicine because of side effects. These patients may anti–IL-1 treatment leads to instant abortion of inflammation
benefit from IL-1 inhibition. 22 with clinical response within the first hours to days after the