Cold Urticaria Syndromes: Diagnosis and Management.

Cold urticaria is a chronic condition causing episodic symptoms of cold-induced wheals or angioedema in response to direct or indirect exposure to cold temperatures. Whereas symptoms of cold urticaria are typically benign and self-limiting, severe systemic anaphylactic reactions are possible. Acquired, atypical, and hereditary forms have been described, each with variable triggers, symptoms, and responses to therapy. Clinical testing, including response to cold stimulation, helps define disease subtypes. More recently, monogenic disorders characterized by atypical forms of cold urticaria have been described. Here, we review the different forms of cold-induced urticaria and related syndromes and propose a diagnostic algorithm to aid clinicians in making a timely diagnosis for the appropriate management of these patients.

Blocking the IL-1 receptor reduces cardiac transplant ischemia and reperfusion injury and mitigates CMV-accelerated chronic rejection.

Ischemia-reperfusion injury (IRI) is an important risk factor for accelerated cardiac allograft rejection and graft dysfunction . Utilizing a rat heart isogeneic transplant model, we identified inflammatory pathways involved in IRI in order to identify therapeutic targets involved in disease. Pathway analyses identified several relevant targets, including cytokine signaling by the IL-1 receptor (IL-1R) pathway and inflammasome activation. To investigate the role of IL-1R signaling pathways during IRI, we treated syngeneic cardiac transplant recipients at 1-hour posttransplant with Anakinra, a US Food and Drug Administration (FDA)-approved IL-1R antagonist; or parthenolide, a caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor that blocks IL-1ß maturation. Both Anakinra and parthenolide significantly reduced graft inflammation and cellular recruitment in the treated recipients relative to nontreated controls. Anakinra treatment administered at 1-hour posttransplant to recipients of cardiac allografts from CMV-infected donors significantly increased the time to rejection and reduced viral loads at rejection. Our results indicate that reducing IRI by blocking IL-1Rsignaling pathways with Anakinra or inflammasome activity with parthenolide provides a promising approach for extending survival of cardiac allografts from CMV-infected donors.

Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

BACKGROUND: Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. METHODS: We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. RESULTS: Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase Cγ(2) (PLCγ(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures. CONCLUSIONS: Genomic deletions in PLCG2 cause gain of PLCγ(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.).

Inflammasome and IL-1beta-mediated disorders.

The NLRP3 inflammasome is an intracellular complex that regulates the release of proinflammatory cytokines such as interleukin-1beta in response to exogenous pathogens and endogenous danger signals. Evidence from studies involving human genetics, human ex vivo mononuclear cell responses, and in vivo and in vitro murine models confirms the importance of the inflammasome and interleukin-1beta in the pathogenesis of several inherited and complex diseases. The availability of several effective interleukin-1beta targeted therapies has allowed for successful proof-of-concept studies in several of these disorders. However, many other diseases are likely to be mediated by the inflammasome and interleukin-1beta, providing additional targets in the future.

Rationale and timeliness for IL-1beta-targeted therapy to reduce allogeneic organ injury at procurement and to diminish risk of rejection after transplantation.

Ischemia-reperfusion injury (IRI) involving allograft transplantation and procured organs may in part be induced by stimulation of a newly described innate pro-inflammatory immune system (i.e., NALP-3-inflammasome), which can cause secretion of IL-1beta and subsequent neutrophilic inflammation. Ischemia and/or hypoxia/anoxia can induce anaerobic metabolism with metabolic acidosis and subsequent development of danger signals known to stimulate IL-1beta secretion from the NALP-3 inflammasome. Observations from IRI studies and hereditary auto-inflammatory syndromes with NALP-3 inflammasome mutations suggest that IL-1beta secretion can induce robust neutrophilic inflammation that is responsive to IL-1beta targeted therapy. Based on these observations and data from transplantation studies, it may be timely to consider commercially available IL-1beta targeted biologic therapy to improve allograft tolerance and viability of procured organs.

Familial atypical cold urticaria: description of a new hereditary disease.

BACKGROUND: Acquired cold urticaria (ACU) is usually a self-limited, sporadic, cutaneous disease diagnosed based on history and a positive cold stimulation time test (CSTT) result. We describe 3 unrelated families (A, B, and C) with lifelong atypical cold urticaria distinguished from ACU and familial cold autoinflammatory syndrome. OBJECTIVE: We sought to describe a new hereditary disease of cold urticaria and study its pathogenesis. METHODS: Questionnaires, interviews, physical examinations, skin testing, and biopsies were performed. Absolute values, means, and prevalence percentages of data are reported. RESULTS: Thirty-five subjects are described with familial atypical cold urticaria (FACU; family A, 17; family B, 8; and family C, 10) displaying an autosomal dominant pattern of inheritance. All tested subjects had negative CSTT results. Completed questionnaires from affected and unaffected members of families A and B (n = 35) revealed that all affected subjects had lifelong symptoms that began in early childhood with pruritus, erythema, and urticaria after cold exposure. Angioedema (family A, 23%; family B, 42%) and syncope, near syncope, or both (family A, 46%; family B, 86%) were also present. Triggers included cold atmosphere (100%), aquatic activities (family A, 92%; family B, 100%), handling cold objects (family A, 54%; family B, 71%), and ingestion of cold foods or beverages (family A, 69%; family B, 100%). Skin biopsy specimens demonstrated a mast cell infiltrate with the appearance of degranulation after cold challenge. CONCLUSIONS: FACU is a new cold-induced inherited disease that is different than ACU in its natural history, atmospheric cold elicitation, severity of systemic reactions, and CSTT results. FACU differs from familial cold autoinflammatory syndrome in symptom timing and the absence of fever, chills, and joint pain. The cause is suspected to be mast cell related. Treatment of reactions is similar to that for ACU. Further evaluation of pathogenesis and genetics is warranted.

Ischemic-reperfusion syndromes: biochemical and immunologic rationale for IL-1 targeted therapy.

Ischemic-reperfusion injury (IRI) can affect many organ systems. Examples include strokes, coronary occlusion, accidental hypothermia, compartment syndrome and neonatal hypoxia. To date no mechanism has been fully accepted to explain acute inflammation associated with IRI. There is circumstantial evidence from animal and human ex-vivo cardiac experiments to support the hypothesis that acute inflammation associated with IRI is in part caused by IL-1 beta and/or IL-1 alpha secretion. Danger signal formation, such as uric acid/calcium pyrophosphate crystallization and other cellular stresses, may occur in IRI. These in turn may stimulate innate immune pathways (i.e. cryopyrin-inflammasome; and/ or toll-like receptors 2 and 4) to secrete IL-1 beta. Most IL-1 targeted therapy studies have focused on chronic human diseases and hopefully this discussion will create a framework to encourage use of this therapy in acute inflammation associated with IRI.

Interleukin-1beta targeted therapy in severe persistent asthma (SPA) and chronic obstructive pulmonary disease (COPD): proposed similarities between biphasic pathobiology of SPA/COPD and ischemia-reperfusion injury.

The histopathology of severe persistent asthma and chronic obstructive pulmonary disease is predominantly characterized by neutrophilic inflammation. It is posited that chronic hypoxia from hypoventilation in combination with hypoperfusion and hypercapnia are associated with induction of pulmonary tissue acidosis in SPA and COPD, which in turn provide ideal conditions to induce danger-associated molecular patterns, i.e., crystallized and calcium pyrophosphate. These stimuli in combination with other danger-related biochemical signals are capable of stimulating an innate immune receptor (cryopyrin inflammasome, NALP3) and cause interleukin-1beta secretion with subsequent neutrophilic inflammation. There is evidence to suggest that the mechanisms and pathobiology associated with chronic hypoxia, reduced perfusion and reoxygenation in SPA/COPD may exhibit similarities to the biphasic pathobiology involved in ischemia-reperfusion injury. A rationale is suggested for trials of IL-1beta targeted therapies as an adjunct strategy to control neutrophilic inflammation in these conditions.

Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.

BACKGROUND: Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterised by recurrent episodes of rash, arthralgia, and fever after cold exposure. The genetic basis of this disease has been elucidated. Cryopyrin, the protein that is altered in FCAS, is one of the adaptor proteins that activate caspase 1, resulting in release of interleukin 1. METHODS: An experimental cold challenge protocol was developed to study the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients and to investigate the effects of pretreatment with an antagonist of interleukin 1 receptor (IL-1Ra). ELISA, real-time PCR, and immunohistochemistry were used to measure cytokine responses. FINDINGS: After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1-4 h. Significant increases in serum concentrations of interleukin 6 and white-blood-cell counts were seen 4-8 h after cold challenge. Serum concentrations of interleukin 1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of interleukin 1 protein and mRNA were high in affected skin. IL-1Ra administered before cold challenge blocked symptoms and increases in white-blood-cell counts and serum interleukin 6. INTERPRETATION: The ability of IL-1Ra to prevent the clinical features and haematological and biochemical changes in patients with FCAS indicates a central role for interleukin 1beta in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-kappaB signalling suggests that it might have a role in many chronic inflammatory diseases. RELEVANCE TO PRACTICE: These findings support a new therapy for a disorder with no previously known acceptable treatment. They also offer insights into the role of interleukin 1beta in more common inflammatory diseases.

The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes.

Acquired cold urticaria syndromes represent one of the more common forms of physical urticaria. The syndromes are heterogenous, and a diagnostic classification is presented to facilitate collation for future studies. Acquired cold urticaria represents an excellent reproducible in vivo model to investigate the mechanisms of urticaria. The discussion includes clinical manifestations, laboratory features, pathogenesis, and management of these disorders. A description of familial types, particularly familial cold auto-inflammatory syndrome (FCAS) that is manifested by cold-evoked signs and symptoms of chronic inflammation, is included. FCAS historically has been included with acquired cold urticaria, even though the exanthem of FCAS is maculopapular caused by leukocytic infiltration. FCAS has become an important investigative syndrome, as it represents a reproducible in vivo model of chronic inflammation.

Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P.

Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant inflammatory disease with a high degree of penetrance that is characterized by episodes of rash, arthralgia, fever, conjunctivitis, and leukocytosis after generalized exposure to cold. FCAS was previously mapped to a 10-cM region on chromosome 1q44, and subsequently the gene ( CIAS1) responsible for FCAS was identified. In this paper, we describe the physical and genetic mapping of the FCAS locus, and we report a large ancestral haplotype and a new disease-causing mutation. A BAC contig of approximately 3 Mb was developed and subsequently used for high throughput sequencing. We identified a critical region of 4 cM using rare crossover events in four large North American FCAS families. An unusually large shared haplotype (40 cM) was identified in three of the four families. We found a single heterozygous missense mutation (T1058C=L353P) in exon 3 of CIAS1 in all four families that is responsible for the large majority of FCAS cases described in the literature. We also report a comprehensive list of intragenic single nucleotide polymorphisms. The data provided here will assist others researching the 1q44 region and will aid clinicians in the diagnosis of FCAS.