Discussion
The cold urticaria syndromes are a heterogeneous group of disorders characterized by the development of inflammation following cold exposure. Cold urticaria has a variety of causes and can be classified broadly into acquired and familial cold forms. Acquired cold urticaria may occur as a primary disorder or secondary to another process. Common secondary causes include cryoglobulinemia, infectious diseases (syphilis, rubeola, varicella, hepatitis, and infectious mononucleosis), or certain drugs (penicillin, oral contraceptives, and angiotensin-converting enzyme inhibitors) [
2]. The history of response to cold exposure may give clues to whether a cold-induced urticaria is an acquired cold urticaria or is due to a familial cause. In contrast to the majority of acquired cold urticarias, CAPS is characterized by a delayed response to cold exposure. An early age of onset as well as the presence of fever and symptoms due to complications of CAPS may also help differentiate it from acquired cold urticarias [
2].
A key diagnostic test in the evaluation of cold-induced urticaria is the cold stimulation time test. In this study, a cold stimulus, such as an ice cube in a plastic bag, is applied for five minutes
to the patient's skin, which then is allowed to rewarm. The test is considered positive if a coalescent wheal forms. It then can be repeated with shorter times of cold stimulation to better define the degree of sensitivity. If the test is negative with a five minute application, it may be repeated with a 10-minute application [
2,
3]. The cold stimulation time test does not typically form an urticaria wheal in patients with CAPS as its symptoms, unlike those of acquired cold urticaria, are not mediated by histamine release.
CAPS is a systemic inflammatory disorder occurring as a result of autosomal dominant or
de novo mutations in the gene
NLRP3 (
CIAS1). Mutations in this gene lead to production of an altered form of the protein, cryopyrin. Cryopyrin, as a member of the NALP3 inflammasome, activates caspase-1, which in turn activates IL-1β. These changes are thought to cause a gain-of-function effect of the NALP3 inflammasome, leading to overproduction of IL-1β [
4].
Inflammasome activation and IL-1β overproduction have been implicated in the pathogenesis of a number of diseases, including type 2 diabetes, gout, and rheumatoid arthritis [
5]. A recent trial of IL-1β blockade in people with type 2 diabetes showed improvements in glycemic control and pancreatic β-cell function [
6], and additional studies to better define the potential role of IL-1β blockade in the treatment of diabetes are ongoing. CAPS is a systemic inflammatory disorder affecting a number of organ systems. Most commonly involved is the skin, and a maculopapular, urticaria-like, and usually nonpruritic rash is typical. Skin lesions are seen in the first six months of life in nearly all patients [
7] and at birth in nearly two thirds of patients with CINCA/NOMID [
8]. The onset of symptoms following cold exposure is delayed an average of two and a half hours and duration is up to 12 hours in patients with FCAS, and attacks in MWS last about one to two days [
7,
9]. The correlation of symptoms with cold exposure is less consistent in MWS than in FCAS. CAPS may also affect the musculoskeletal, renal, neurologic, and ocular systems. Joint symptoms range from arthralgias in FCAS to severe joint deformation in CINCA/NOMID. Renal involvement is often seen in patients with MWS and CINCA/NOMID, and elevations in serum amyloid A levels potentially lead to renal amyloidosis in about 25% of patients with MWS [
9]. Ocular involvement consists mainly of conjunctivitis and episcleritis, although blindness may occur in patients with CINCA/NOMID. Progressive sensorineural hearing loss is seen in about 60% of patients with MWS [
9].
Advances in the understanding of the pathogenesis of CAPS resulted in the use of therapies targeting IL-1β in the treatment of this disorder. First developed among these agents was anakinra, a recombinant human IL-1 receptor antagonist. Originally approved for use in rheumatoid arthritis, it reduces the inflammation associated with CAPS [
10,
11]. Anakinra has been shown to improve symptoms of CAPS and also may reverse or stabilize hearing loss and renal amyloidosis due to CAPS [
12]. The symptomatic improvements seen with anakinra, however, are contingent upon continued daily administration, and withdrawal leads to a re-emergence of symptoms [
10,
11].
Rilonacept, a fusion protein of the extracellular IL-1 receptor and the Fc portion of human IgG1, is a newer alternative therapy. This agent traps IL-1, binding it and preventing it from interacting with the IL-1 receptor. Its high affinity for IL-1β allows once-weekly dosing [
13]. The safety and efficacy of rilonacept were evaluated in two randomized, placebo-controlled trials, in which rilanocept therapy resulted in rapid and sustained improvement of symptoms. Serum amyloid A and C-reactive protein levels also were reduced with rilonacept. The most common adverse events seen with rilonacept therapy are injection site reactions and upper respiratory infections [
14].
Canakinumab is the newest medication released for the treatment of CAPS. This agent is a fully human anti-IL-1β monoclonal antibody with a plasma half-life of 28 to 30 days, allowing dosing once every eight weeks. In a randomized, double-blind, placebo-controlled trial, canakinumab administration led to rapid and sustained reduction of inflammatory symptoms and normalization of serum amyloid A levels in patients with CAPS. Canakinumab was well tolerated and caused few injection site reactions, although the incidence of suspected infection was higher versus placebo [
15].
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
JCF performed the literature review and co-authored the manuscript. MP co-authored the manuscript. Both authors read and approved the final manuscript.