Urticaria/Hives : Variants, Symptoms and treatment
Urticaria is also known as hives. It is the most frequent dermatologic disorder or skin rash characterized by raised, well-circumscribed areas of erythema (redness) and edema (swelling) involving the dermis and epidermis that are very pruritic.
Urticaria may be acute (lasting less than 6 weeks) or chronic (lasting more than 6 weeks).
Variants of urticaria
A large variety of urticaria variants exist, including
- Acute immunoglobulin E (IgE)–mediated,
- Chemical-induced (non-IgE-mediated),
- Autoimmune urticaria,
- Cholinergic urticaria,
- Cold urticaria,
- Periodic fever syndromes including Muckle-Wells syndrome,
While acute urticaria is generally related to an exogenous allergen or acute infection, chronic urticaria is more likely to be associated with autoimmunity.
The condition is not contagious unless the swollen hives themselves contain a pathogen.
It may be confused with a variety of other dermatologic diseases that are similar in appearance and are pruritic including atopic dermatitis (eczema), maculopapular drug eruptions, contact dermatitis, insect bites, erythema multiforme, pityriasis rosea, urticarial vasculitis, and others.
It is common, affecting 10–20% of individuals at some time. Urticaria depends on mast cells and histamine is the principal mediator. The reaction may be due to IgE on mast cells or stimuli that directly activate mast cells.
It may occur alone or be accompanied by more systemic symptoms, including angioedema, although histamine is not involved in the latter.
It may be acute or chronic.
Chronic urticaria is often idiopathic (75% of cases) and rarely associated with allergy. 5% of the population may develop physical urticaria. Idiopathic urticaria may disappear spontaneously after 1–2 years.
The most common causes are as follows.
- Infections: in association with common viral infections (concomitant drug therapy usually gets the blame!); Helicobacter pylori; prodrome of hepatitis B, Lyme disease, cat-scratch disease; acute or chronic bacterial infections; parasitic infections.
- Allergic: ingested allergens, injected allergens (e.g. cat scratch).
- Autoimmune: autoantibodies to IgE and to Fc RI (probably rare); also in association with connective-tissue diseases (antibodies to C1q): SLE.
- Cold: familial (autosomal dominant—C1AS1 gene mutations ); acquired (cryoglobulins, cryofibrinogen, mycoplasma infections).
- Cholinergic (much smaller wheels, often triggered by heat and sweating).
- Adrenergic: provoked by stress.
- Contact (e.g. urticaria from lying on the grass, wearing latex gloves, occasionally from aero-allergens).
- Urticaria pigmentosa: a rare disease with reddish-brown macules in the skin (accumulations of mast cells).
- Vasculitis: usually a leukocytoclastic vasculitis, painful not itchy; also serum sickness (immune complex).
- Hormonal: autoimmune progesterone-induced urticaria related to menstrual cycle; occasionally other steroids may cause the same reaction; hypothyroidism.
- Papular urticaria: related to insect bites.
- Rare syndromes: Muckle-Wells and related syndromes; mastocytosis ); PUPP (pruritic urticaria and plaques of pregnancy).
- Urticaria may occur with iron, B12, and folate deficiency.
Mast-cell activation is the cause, with local release of mediators and activation of other pathways, complement, and kinin.
Autoantibodies against IgE and the IgE receptor (FcεRI) have been proposed as a mechanism in some patients with chronic urticaria. These lead to the activation of mast cells by cross-linking surface IgE or receptors. How generally applicable this mechanism remains to be determined. Assays are dubious.
Mast cells can be stimulated through other pathways, either directly by drugs or by the anaphylatoxins C3a, C5a (type II) and by immune complexes (type III).
In cholinergic urticaria mast cells are unusually sensitive to stimulation by acetylcholine released by local cholinergic nerves.
The history and physical examination are key in diagnosis
The appearances of the lesions may give clues (distinctive lesions in cholinergic urticaria).
Dermographism should be sought.
Physical causes can usually be replicated in the clinic to confirm the diagnosis: pressure tests; ice cube test (wrap ice cube in a plastic bag to ensure that it is cold and not water that causes the problem).
Other diagnostic tests should depend on likely cause.
Allergy testing is rarely justified in chronic urticaria as the yield is low.
Check thyroid function, acute-phase response, and full blood count, and think of infective causes.
Foods may play a role in acute urticarias; exclusion diets may help but only if there is a strong suspicion on clinical grounds. The role of natural dietary salicylates and/or preservatives in chronic urticaria is controversial.
In cold urticaria, seek family history and check for cryoglobulins and causes thereof (electrophoresis of serum, search for underlying diseases, infections, connective tissue disease, lymphoproliferation).
Autoantibodies (ANA, ENA, dsDNA, RhF) and complement studies (C3, C4) may be relevant in some instances. In SLE with urticaria, think of autoantibodies to C1q.
A skin biopsy should be considered if there are atypical features if urticarial vasculitis is suspected
Treatment of urticaria
Urticaria may be difficult to manage, especially cold urticaria.
A most common failing is an inadequate dosage of antihistamines. The new antihistamines are safe in doses well above the recommended doses and do not interfere with cardiac potassium channels, causing prolonged QT interval.
Acute urticaria should be treated with potent non-sedating antihistamines. Short-acting antihistamines such as acrivastine may be appropriate for intermittent attacks. Potent long-acting non-sedating antihistamines, such as fexofenadine, levocetirizine, and cetirizine, are useful for prophylaxis against frequent attacks. A few patients may still be sedated by these drugs.
Loratadine and desloratadine have been reported by the EMA to be possibly associated with a small increase in minor malformations if taken in pregnancy. Doses up to four times the normal dose may be required in difficult cases.
If antihistamines are unsuccessful alone, the addition of an H2-blocker may be helpful, although the evidence is weak. There is no evidence to suggest whether ranitidine or cimetidine is preferable.
Other therapeutic options
Other therapeutic options include the following.
Doxepin, an antidepressant with potent H1- and H2-blocking activity.
Ketotifen, which has mast-cell stabilizing activity in addition to anti-H1 activity (it increases appetite and is sedating).
Mirtazapine is also a valuable third-line agent and has antihistaminic properties.
Calcium-channel blockers may have some beneficial effect as they stabilize mast cells (nimodipine is said to be better than nifedipine).
B2-agonists (terbutaline) and phosphodiesterase inhibitors (theophylline) may help in rare cases. Pentoxifylline has been reported to reduce cytokine synthesis by macrophages and may be helpful.
Colchicine is helpful in delayed pressure urticaria but is poorly tolerated.
Leukotriene antagonists may also be helpful in some patients.
Modified androgens (stanozolol, danazol) require monitoring of liver function testing.
Methotrexate reduces neutrophil accumulation and decreases leukotriene synthesis.
Non-familial cold urticaria may respond to cyproheptadine, calcium-channel blockers, B2-agonists, and phosphodiesterase inhibitors, although responses tend to be poor.
Familial cold urticaria does not respond to antihistamines but may respond to NSAIDs.
Steroids may be effective but should be used as a last resort as chronic therapy is not justified by the side effects. Short courses may be helpful for acute disease. Withdrawal of steroids is often marked by worse flares of rash.
Ciclosporin or tacrolimus may also be helpful, but the disease relapses once the drug is withdrawn. The side effects (hypertension, nephrotoxicity) make them undesirable drugs for urticaria unless symptoms are severe. Mycophenolate has also been used.
High-dose IVIg has been used in resistant cases but the benefits are variable.
Whenever chronic therapy is started, it is important to withdraw it at intervals to see whether it is still required in the light of possible spontaneous remission.