Urticaria, Angioedema and Autoinflammatory Syndromes
Urticaria are pruritic wheals or swellings and are generally known as hives. The new classification includes Acute Spontaneous (ASU) less than 6 weeks duration, Chronic Spontaneous (CSU) greater than 6 weeks duration and Chronic Inducible Urticaria (CINDU) triggered by specific stimuli (cold temperature, physical pressure, increased core body temperature). ASU is a common condition affecting 20-30% of the population at some time. CSU is more common than previously thought and is increasing. At any single time 0.5-1% of children and adults are suffering with CSU. This is a debilitating disease with over half having moderate to severe disease activity with a poor quality of life. Chronic Urticaria markedly impairs daily activities , sleep quality and work productivity. Over 20% report significant time loss from work and economic losses.
The treatment response to H1 antihistamines supported the role for mast cell derived histamine in the development of an urticarial lesion. This is supported by recent evidence of increased dermal mast cell number, with degranulation resulting in increased inflammatory mediators within urticarial lesions.
The finding of thyroid auto-antibodies in chronic urticaria was an early observation that CSU was not an allergy but an auto-immune disease. It has since been shown that this includes two possible forms type 1 and type 2b.
The potential role of IgE type-1 autoimmunity or autoallergy was hypothesized with the observation of IgE to thyroperoxidase with the subsequent reporting of IgE to double-stranded DNA and interleukin 24. The recent observation that CSU patients have elevated serum IgE supported autoallergy mediated mast cell degranulation. The fast onset of action and almost complete control of urticaria activity with anti IgE (Omalizumab) treatment is often seen in patient sub population.
IgG auto-antibodies (Type 2b) have been found in about 40% of CSU patients. These IgG antibodies are directed to the patients IgE or the high affinity (FcɛRI) mast receptors causing degranulation with urticarial wheals. Type 2b autoimmune urticaria can be better defined with the use of novel in vivo and in vitro testing and markers.
Type 2b autoimmune CSU results in wheals with intradermal injection of patient’s serum or auto reactivity (autologous serum skin test). A positive basophil histamine release (BHRA) and basophil activation test (BAT) is also seen as well as IgG autoantibodies against mast cell receptors (FcɛRI) in this urticaria subset.
As we continue to better define and understand these immunologic mechanisms and phenotypes we are able to better treat this condition.
New evidence based international guidelines have been developed to disseminate this new understanding including classification, diagnostic work up, and treatment. The urticaria guidelines are representive of 43 international experts from 25 countries and are updated every four years..
Urticarial wheals are often accompanied (about 50%) with a deeper swelling or angioedema. The disfiguring angioedema further impairs the quality of life seen in CSU. However unlike bradykinin induced angioedema seen in hereditary angioedema (HAE), the swelling is not life threatening.
Another category of disease which may present as urticarial wheals are the autoinflammatory diseases caused by gain of function mutations of IL1 with resulting inflammatory diseases. These conditions are associated with elevated inflammatory markers and are identified using genetic testing . New markers and diseases are being continually discovered. These diseases are associated with systemic symptoms including fever, bone pain, and fatigue. The treatment is with IL1 receptor antagonists.
Evidence based treatment starts with only non sedating, non impairing second generation antihistamines. The doses of these H1 antihistamines be increased up to four fold without increased toxicity. However about 40-50% of patients with CSU are still unresponsive to these medications. First generation antihistamines are sedating are sedating and impairing and are no longer recommended as treatment.
Third line of treatment is omalizumab, a humanized anti-IgE monoclonal antibody, which was initially developed to treat allergic asthma. Using Omalizumab we can treat up to 85% of CSU patients even those who were refractory to H1 antihistamines. We generally treat until the disease is in remission or gone.. CSU is characterized by exacerbations and remissions when all medication can be stopped. However about 10-25% of CSU patients have the disease activity for longer than 5 years.
Fourth line treatment with low dose cyclosporine (3-5mg/kg) can be used with careful monitoring for toxicity. . Many other treatments are available for refractory patientswhich have been shown to be effective in smaller numbers of patients. H2 antihistamines and leukotriene antagonists are no longer on the treatment algorithm because of poor evidence for efficacy. Prednisone and other corticosteroids are not treatments but interventions that can be used if needed for short periods of time.
In summary our understanding of urticaria has significantly changed in the past 10 years. Urticaria is a mast cell mediated disease causing significant disability with defined immunologic and autoimmune pathogenesis . New treatments have been licienced and new medications are being developed to better treat this debilitating disease.