Case 1. Urticaria in infancy
The patient was a female infant who was the product of a di-zygotic twin pregnancy with no known complications.9 The perinatal period was uneventful. The baby was in a normal state of health until 3 months of age, when she developed a raised, erythematous rash diagnosed as dermatographism. The rash resolved without medical intervention, but recurred at age 9 months, for which she was treated with antihistamines, as needed, for idiopathic urticaria. There were no known exposures, and intermittent therapy with antihistamines was successful. At 14 months of age, the patient developed an acute episode with prominent urticarial-like rash, 8 days of fever to a maximum temperature of 104.1ï‚°C, conjunctival infection, and irritability. She was admitted to a tertiary care children™s hospital with a presumptive diagnosis of Kawasaki disease. Physical exam on admission was notable for a well-developed, well-nourished child with tachycardia, scattered lymphadenopathy, hepatosplenomegaly, and multiple erythematous, blanchable macules, and patches of an urticarial nature, mostly involving the face, torso, and extremities with relative sparing of the palms and soles. Clinical laboratory evaluation revealed elevated inflammatory markers, leukocytosis with neutrophilia, and thrombocytosis. Her infectious workup was negative and multiple echocardiograms were normal. Her fever and rash did not improve, despite high dose intravenous immunoglobulin (IVIG). A skin biopsy was performed which demonstrated a mixed perivascular inflammatory infiltrate comprised of lymphocytes, neutrophils, and rare eosinophils, without evidence for vasculitis, suggesting a diagnosis of cryopyrin-associated periodic syndrome.10
Cryopyrin-associated periodic syndromes (CAPS)
Cryopyrin-associated periodic syndromes (CAPS) include a spectrum of autoinflammatory diseases caused by autosomal dominant mutations in NLRP3 which encodes the NLRP3 protein.11 Mutations in NLRP3 lead to increased activity of the cryopyrin protein with over-production of the inflammatory mediator IL-1ï¢.12,13 The CAPS spectrum consists of familial cold autoinflammatory syndrome (FCAS) on the mild end,10 Muckle Wells syndrome as moderate disease,14 and neonatal-onset multisystem inflammatory disease (NOMID) on the severe end.15 Common symptoms include an urticaria-like rash, intermittent fevers, conjunctivitis, arthralgia, headache, and fatigue but certain phenotypic features may suggest mild vs. moderate vs. severe disease.16 Patients with the milder FCAS, tend to have 12-24 hour attacks, with urticaria-like rash, polyarthralgia, and conjunctivitis, often triggered by cold temperatures. The moderate Muckle-Wells syndrome episodes tend to be longer in duration (2-3 days) and have the addition of sensorineural deafness, often presenting in the second decade of life.14 Finally, NOMID, also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is characterized by continuous symptoms of fever, urticaria-like rash, uveitis with vision loss, sensorineural deafness, chronic aseptic meningitis, and epiphysial overgrowth. Despite the differences in severity, all result in activation of the NLRP3 sensor and release of IL-1ï¢ which drives the autoinflammatory loop.16 Three different biologic therapies are currently available to treat patients with CAPS: a recombinant IL-1 receptor antagonist (anakinra), a fusion protein of IL-1 receptor and IL-1 receptor accessory protein (rilonacept), and a humanized monoclonal antibody to IL-1ï¢ (canakinumab). For patients with CAPS, IL-1 blockade has consistently led to a reduction of symptomatic periods and inflammatory markers (reviewed in Booshehri and Hoffman, 201916). In addition, early diagnosis and initiation of anti“IL-1 therapy has often shown substantial improvement of progressive and long-term complications of CAPS, including hearing loss and renal disease, as well as improvement in quality of life measures.17,18
Inflammasomes and the molecular mechanisms behind CAPS
NLRP3 is part of the NOD-like receptor (NLR) family of innate immune receptors. These proteins have a similar domain structure consisting of an effector, switch, and sensor domain.19,20 Together, they act as intracellular sensors of pathogens and danger signals. In a two-signal process, cells respond to PAMPs or endogenous cytokines to increase transcription of pro-cytokine forms of IL-1ï¢ and IL-18, as well as the molecules of the inflammasome. The second signal by extracellular ATP, pore-forming toxins, or crystals (including urate, silica, asbestos, or cholesterol), leads oligomerization of the NLRP3 sensor with an adaptor protein (ASC) and an enzyme effector (caspase-1) to form a multimeric cytosolic protein. This process ultimately leads to cleavage of caspase-1 which acts to cleave pro-cytokines to their mature, active forms.12,13 In CAPS, a mutation in NLRP3 results in inflammasome activation in the absence of the second signal.21,22 However, the varied nature of the stimuli leading to activation of the NLRP3 inflammasome has led to implications for its involvement in numerous more chronic diseases including gout, pseudogout, asbestosis, silicosis, atherosclerosis, and type 2 diabetes (reviewed in Broderick et al., 201523).
Since the identification of the NLRP3 inflammasome, several additional sensor proteins, including NLRP1, NLRC4, AIM2, and pyrin, and their associated inflammasomes have been identified, that respond to other innate immune pathways, though their triggers seem to be less varied than those for NLRP3. The NLRP1 inflammasome is activated by anthrax toxin. NLRC4 is triggered by type III/IV bacterial secretion systems and flagellin.24,25 AIM2 senses cytoplasmic double-stranded DNA (of either host or microbial origin),26 and the pyrin sensor detects Rho-GTPase modifications of host proteins mediated by bacterial toxins including C. difficile.27 Subsequently, monogenic diseases have been linked to mutations in the genes for these sensors. NLRP1 variants have been linked to NLRP1-associated autoinflammation arthritis and dyskeratosis.28 NLCR4 mutations are associated with macrophage activation syndrome and enterocolitis, as well as a CAPS-like disease,24,25 and mutations in pyrin cause familial Mediterranean fever29,30 and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND).31 A monogenic disease linked to variants in AIM2 has yet to be identified.