What is chronic urticaria

Urticaria or hives are red, itchy welts that result from a skin reaction. The welts vary in size and appear and fade repeatedly as the reaction runs its course. Urticaria can be itchy; sometimes they also burn or sting. Usually, they’re harmless and last anywhere from half an hour to a couple of days. New urticaria can show up to replace the old ones as they fade, though. So the condition can go on for a while.

Up to 20 percent of people get occasional urticaria. Some are the result of allergies or other physical causes, but for majority of people the cause is unknown—the medical term for which is “idiopathic” — no external cause or underlying disease process can be identified. Several theories regarding the pathogenesis of chronic urticaria exist but none has been conclusively established. It is a disease that can be frustrating to treat for both patients and caregivers, and it can have a detrimental effect on quality of life.

The condition is considered chronic urticaria if the welts appear for more than six weeks and recur frequently over months or years. Often, the cause of chronic urticaria is not clear ¹. And the medical diagnostic term for those of unknown cause is “chronic idiopathic urticaria”.

In the general population, the prevalence of chronic urticaria is estimated to be around 0.5-5%. Chronic urticaria is more frequently seen in females ².

Patients with chronic urticaria have a strong association with HLA-DR4 and the associated allele HLA-DQ8 compared with a control population ³.

Chronic urticaria can be very uncomfortable and interfere with sleep and daily activities. For many people, antihistamines and anti-itch medications provide relief.

Chronic urticaria may be divided into three primary subgroups, as follows:

• Physical urticaria/inducible urticaria (ie, symptomatic dermatographism, cholinergic urticaria, pressure urticaria)
• Urticaria secondary to an underlying medical condition
• Chronic idiopathic urticaria/chronic spontaneous urticaria

About 20% of patients with chronic urticaria have physical urticaria, in which the appearance of lesions is triggered by a consistent identifiable factor. Physical urticaria is reproducible with the appropriate stimuli, and it can be identified with a thorough history, physical examination, and challenge testing. Some examples of direct triggers include mechanical stimuli, temperature changes, sweating, stress, sun exposure, and water contact.

When a physical etiology has been excluded, the traditional approach has been to order a panel of laboratory tests to uncover an occult medical condition responsible for the skin findings. In many patients, an extensive workup does not uncover an etiology. In systematic review of 6462 patients with chronic urticaria, a causative internal medical condition was found in only 1.6% of patients ⁴ .Urticaria rarely is the sole manifestation of an underlying medical problem.

The largest subset of patients with chronic urticaria encompasses patients in whom no explanation for their urticaria is definitively established. Traditionally, these patients were said to have chronic idiopathic urticaria; however, findings suggest that about 20-45% of such patients may have an underlying autoimmune process driving their disease, and this specific cohort of patients is said to have chronic autoimmune urticaria. Chronic spontaneous urticaria is a newer label used to refer to all patients with either chronic idiopathic urticaria (55%) or chronic autoimmune urticaria (45%) ⁵.

An important entity in the differential diagnosis of chronic urticaria is urticarial vasculitis. A forme fruste of leukocytoclastic vasculitis, urticarial vasculitis may be associated with hypocomplementemia and systemic symptoms. If urticarial lesions persist for more than 24 hours, biopsy should be performed to rule out this entity histologically.

Figure 1. Chronic urticaria

Symptoms of chronic urticaria

Urticarial lesions are transient in nature, with individual wheals typically lasting for less than 24 hours. Pruritus (itchy skin) is the most common associated symptom of chronic urticaria.

Signs and symptoms of chronic urticaria include:

• Batches of red or skin-colored welts (wheals), which can appear anywhere on the body
• Welts that vary in size, change shape, and appear and fade repeatedly as the reaction runs its course
• Itching, which may be severe
• Painful swelling (angioedema) of the lips, eyelids and inside the throat
• A tendency for signs and symptoms to flare with triggers such as heat, exercise and stress
• A tendency for signs and symptoms to persist for more than six weeks and to recur frequently and unpredictably, sometimes for months or years

Short-term (acute) hives appear suddenly and clear up within a few weeks.

When to see a doctor

See your doctor if you have severe hives or hives that continue to appear for several days.
Seek emergency medical care

Chronic urticaria don’t put you at any sudden risk of a serious allergic reaction (anaphylaxis). If you do experience hives as part of a serious allergic reaction, seek emergency care. Signs and symptoms of anaphylaxis include dizziness, trouble breathing, and swelling of your lips, eyelids and tongue.

Chronic urticaria causes

The welts that come with hives arise when certain cells release histamine and other chemicals into your bloodstream.

Doctors often can’t identify the reason for chronic hives or why acute hives sometimes turn into a long-term problem. The skin reaction may be triggered by:

• Pain medications
• Insects or parasites
• Infection
• Scratching
• Heat or cold
• Stress
• Sunlight
• Exercise
• Alcohol or food
• Pressure on the skin, as from a tight waistband

In some cases, chronic hives may be related to an underlying illness, such as a thyroid disease or rarely, cancer.

Autoimmunity is thought to be one of the most frequent causes of chronic urticaria. Various autoimmune or endocrine diseases have been associated with urticaria, including systemic lupus erythematosus, cryoglobulinemia, juvenile rheumatoid arthritis, and autoimmune thyroid disease (eg, Graves disease) ⁶.

Several cross-sectional studies have investigated whether patients with chronic urticaria are more prone to autoimmune disorders. Ryhal et al ⁷ compared 25 patients with urticaria with 75 subjects being treated for other conditions and found that antibodies to thyroid peroxidase (also known as thyroid microsomal antibody) and rheumatoid factor were more common in patients with chronic urticaria compared with controls. However, no difference was reported in the prevalence of other autoantibodies, such as anti-sDNA, anti-Ro/anti-La ribonucleic acid antibodies, anti-cardiolipin, anti–β2-glycoprotein 1, antimyeloperoxidase, anti–proteinase 3, anti–smooth muscle, and antinuclear antibodies, between the two groups. These data imply that broad nonspecific autoantibodies are not commonly found in patients with chronic urticaria.

There is a significant association of chronic urticaria with thyroid autoimmunity, and antithyroid autoantibodies are significantly increased in patients with chronic urticaria. The prevalence of thyroid autoimmunity among chronic urticaria patients varies from 4.3% to 57% in the literature, and about 5-10% of chronic urticaria patients have abnormal thyroid function ⁸. In one study comparing 70 patients with chronic urticaria with 70 healthy controls, it was found that 23-30% of patients with chronic urticaria had either or both antithyroglobulin antibody (anti-Tg) and antimicrosomal antibody (antithyroid peroxidase [TPO]), and as many as 5-10% had abnormal thyroid function ⁸. A case control study detected similar rates of thyroid antibodies in chronic urticaria patients, detecting anti-TG positivity in 22% and anti-TPO positivity in 27% of chronic urticaria patients; 93% of patients had normal thyroid function ⁹.

Although thyroid autoantibodies are identified more frequently in patients with chronic urticaria compared with the general population, there is no clear evidence that management of chronic urticaria or the course of chronic urticaria differs in this subgroup, nor is there persuasive evidence that administration of thyroid hormone supplementation in such cases is associated with improved outcomes. Because the clinical relevance of these autoantibodies for evaluation and treatment of patients with chronic urticaria has not been established, routine testing for thyroid autoantibodies is not recommended ².

Urticaria may be caused or exacerbated by a number of drugs. Among the more common culprits are aspirin and other NSAIDs, opioids, angiotensin-converting enzyme (ACE) inhibitors, and alcohol.

Urticaria has been reported to be associated with a number of infections; however, these associations are not strong and may be spurious. Infectious agents reported to cause urticaria include hepatitis B and C viruses, Streptococcus and Mycoplasma species, Helicobacter pylori ¹⁰, Mycobacterium tuberculosis, and herpes simplex virus (HSV).

There is limited evidence that if H pylori colonization is present, eradication may result in an improvement in chronic urticaria symptoms and thus, screening for H pylori is not recommended ¹¹.

The nematode Anisakis simplex is often the cause of chronic urticaria in areas where the population frequently consumes raw or marinated fish. A report of adults seen at an allergy center in Bari, Italy, found that 106 (50%) of 213 patients with chronic urticaria had A simplex hypersensitivity; all of the hypersensitive patients regularly ate marinated fish. In comparison, only 16% of a control population without chronic urticaria had sensitization to A simplex ¹². Chronic urticaria disappeared in 82 (77%) of 106 patients who gave up raw fish for 6 months; the condition cleared up in only one (2%) of 42 patients who did not give up raw fish. Additionally, 88% who returned to eating raw fish after their condition disappeared had a relapse of chronic urticaria, compared with 14% of those who remained on the diet ¹².

Some patients report the onset of acute urticaria associated with the consumption of certain foods, such as shellfish, eggs, nuts, strawberries, or certain baked goods. However, food allergy is rarely the basis of chronic urticaria.

Contactants may give rise to contact urticaria syndrome, a term referring to the onset of urticaria within 30-60 minutes of contact with an inciting agent. The lesions may be localized or generalized. Precipitating agents include latex (especially in healthcare workers), plants, animals (eg, caterpillars, dander), medications, and food (eg, fish, garlic, onions, tomato).

Arthropod bites or stings are the most common cause of papular urticaria. Although patients who are bitten by mosquitoes are likely to be aware of the source of the problem, patients with scabies, bedbug bites, flea bites, or other similar problems may not be aware. Ask patients about exposure to animals, recent moves, hobbies, travel, or the presence of a similar skin condition in other members of the household.

Urticaria is a feature of some autoinflammatory diseases, such as Muckle-Wells syndrome (characterized by amyloidosis, nerve deafness, and urticaria) and Schnitzler syndrome ¹³ (characterized by fever, joint or bone pain, monoclonal gammopathy, and urticaria).

Little evidence exists to support the concern that chronic urticaria may be a cutaneous sign of occult internal malignancy. In a study of 1155 patients with chronic urticaria in Sweden, Sigurgeirsson found no association with cancer, although acquired angioedema associated with C1 inhibitor depletion may be associated with malignancy ¹⁴. In a population-based cohort study in Taiwan, a slightly increased risk of cancer, especially hematologic malignant tumor, was observed among patients with chronic urticarial ¹⁵. However, evidence is not sufficient to suggest any causality. Routine screening for malignancies in chronic urticaria is not suggested; it is only warranted if patient history dictates.

In approximately 20% of cases, physical factors can be identified as a consistent cause or trigger for chronic urticaria. The various types of physical urticaria are diagnosed by challenge testing. Several types exist, and it is not uncommon to find that a single patient has more than one type. The following are some of the types of physical urticaria, along with their triggers:

• Dermatographism (dermographism) – Firm stroking
• Delayed pressure urticaria – Pressure
• Cold urticaria – Cold
• Aquagenic urticaria – Water exposure
• Cholinergic urticaria – Heat, exercise, or stress
• Solar urticaria – Sun exposure (visible light and/or UV)
• Vibratory urticaria – Vibration

Neurologic factors may play a causative role. An Italian study reported an association between chronic urticaria and fibromyalgia, and the authors suggested that chronic urticaria may be a consequence of fibromyalgia-neurogenic skin inflammation ¹⁶.

Emotional and psychological factors are reported to play a role in a number of patients. Some reports cite improvement of symptoms with hypnotism; however, the role of emotional factors remains controversial.

Hereditary angioedema is characterized by recurrent attacks of angioedema (without urticaria) involving the skin, gastrointestinal (GI) tract, respiratory tract, and mucous membranes in a patient with a positive family history. The disorder is autosomal dominant, and it is caused by a functional deficiency of the C1 inhibitor protein.

Complications of chronic urticaria

Chronic urticaria don’t put you at any sudden risk of a serious allergic reaction (anaphylaxis). As a rule, lesions of urticaria should resolve without complications; however, patients with severe pruritus may develop scratch purpura and excoriations that may become secondarily infected. Additionally, antihistamine use may cause somnolence and dry mouth.

But if you do experience hives as part of a serious allergic reaction, seek emergency care. Signs and symptoms of anaphylaxis include dizziness, trouble breathing, and swelling of your lips, eyelids and tongue.

Prognosis of chronic urticaria

The primary manifestations of urticaria are rash and pruritus. The course of the disease is unpredictable, and it may last months to years. About 50% of patients experience remission within 1 year ¹⁷. Only rarely does permanent hyperpigmentation or hypopigmentation occur. The only long-term consequences of chronic urticaria are anxiety and depression.

The prognosis in chronic urticaria depends on the comorbid disease causing the urticaria and the patient’s response to therapy. Several diseases associated with chronic urticaria can be associated with significant morbidity and mortality (eg, malignancies, systemic lupus erythematosus). Chronic urticaria can affect the patient’s quality of life, owing to the associated pruritus and loss of sleep. It can lead to anxiety and depression, with rare reports of suicide.

Diagnosis chronic urticaria

The diagnosis of chronic urticaria is largely clinical and based on a thorough history and physical examination.

Your doctor will do a physical exam and ask you a number of questions to try to understand what might be causing your signs and symptoms. He or she may also ask you to keep a diary to keep track of:

• Your activities
• Any medications, herbal remedies or supplements you take
• What you eat and drink
• Where hives appear and how long it takes a welt to fade
• Whether your hives come with painful swelling

If your physical exam and medical history suggest your hives are caused by an underlying problem, your doctor may have you undergo testing, such as blood tests or skin tests and these include the following:

• Complete blood cell (CBC) count with differential: The eosinophil count may be elevated in patients with parasitic infections, especially in developing countries, or in patients experiencing a drug reaction
• Examination of the stool for ova and parasites: Should be considered in patients with gastrointestinal tract symptoms, an elevated eosinophil count, or a positive travel history
• Erythrocyte sedimentation rate (ESR): May be elevated in persons with urticarial vasculitis
• Antinuclear antibody (ANA) titers: Indicated when urticarial vasculitis is suspected
• Hepatitis B and C titers: Hepatitis B and C may be associated with cryoglobulinemia, which is associated with some forms of cold-induced urticaria and urticarial vasculitis
• Serum cryoglobulin and complement assays: Cryoglobulinemia is associated with some forms of cold-induced urticaria
• Complement assays: C3 (associated with pulmonary involvement in a subset of patients with urticarial vasculitis), C4 (sometimes low in hereditary angioedema), and C1-esterase inhibitor (associated with hereditary angioedema) functional assays may be performed
• Thyroid function testing and antithyroid microsomal and peroxidase antibody titers: Patients with urticaria unresponsive to antihistamines or steroids may have elevated titers ¹⁸ ; the plasma thyrotropin level (TSH) helps screen for thyroid dysfunction
• Chronic Urticaria (CU) Index: A nonspecific measure of basophil histamine release, which, if positive, may indicate the presence of an autoantibody to the Fc receptor of immunoglobulin E (IgE)—that is, anti-FceR. These patients are likely to have an autoimmune basis for their disease

A skin biopsy is necessary in cases of suspected urticarial vasculitis or in cases of urticaria with atypical features on history and examination. It is also indicated for patients in whom individual urticarial lesions persist for more than 24 hours or are associated with petechiae or purpura, as well as for patients with systemic symptoms such as fever, arthralgia, or arthritis. A neutrophil-predominant pattern of urticaria on biopsy may represent a subtype that does not respond well to antihistamines.

Treatment of chronic urticaria

Your doctor will likely recommend you treat your symptoms with home remedies, such as over-the-counter antihistamines. If self-care steps don’t help, talk with your doctor about finding the prescription medication or combination of drugs that works best for you. Usually, an effective treatment can be found.

Antihistamines

Taking nondrowsy antihistamine pills daily helps block the symptom-producing release of histamine. They have few side effects. Examples include:

• Loratadine (Claritin)
• Fexofenadine (Allegra)
• Cetirizine (Zyrtec)
• Desloratadine (Clarinex)

If the nondrowsy antihistamines don’t help you, your doctor may increase the dose or have you try the type that tends to make people drowsy and is taken at bedtime. Examples include hydroxyzine pamoate (Vistaril) and doxepin (Zonalon).

Check with your doctor before taking any of these medications if you are pregnant or breast-feeding, have a chronic medical condition, or are taking other medications.

Other medications

If antihistamines alone don’t relieve your symptoms, other drugs may help. For example:

• Histamine (H-2) blockers. These medications, also called H-2 receptor antagonists, are injected or taken orally. Examples include cimetidine (Tagamet HB), ranitidine (Zantac) and famotidine (Pepcid).
• Anti-inflammation medications. Oral corticosteroids, such as prednisone, can help lessen swelling, redness and itching. These are generally for short-term control of severe hives or angioedema because they can cause serious side effects if taken for a long time.
• Antidepressants. The tricyclic antidepressant doxepin (Zonalon), used in cream form, can help relieve itching. This drug may cause dizziness and drowsiness.
• Asthma drugs with antihistamines. Medications that interfere with the action of leukotriene modifiers ¹⁹, ²⁰ may be helpful when used with antihistamines. Examples are montelukast (Singulair) and zafirlukast (Accolate).
• Colchicine and dapsone: May help patients who respond poorly to antihistamine therapy or who are known to have urticaria in which the inflammatory infiltrate is neutrophil-predominant.
• Levothyroxine: May benefit some patients with chronic urticaria, antithyroid antibodies, or Hashimoto thyroiditis
• Man-made (monoclonal) antibodies. The drug omalizumab (Xolair) is very effective against a type of difficult-to-treat chronic hives. It’s an injectable medicine that’s usually given once a month.
• Immune-suppressing drugs. Options include cyclosporine (Gengraf, Neoral, others) and tacrolimus (Astagraft XL, Prograf, Protopic).
• Vitamin D. High-dose vitamin D add-on therapy may provide relief in some patients with chronic urticaria. In a 12-week prospective study of 42 patients with chronic therapy receiving standard triple-drug therapy (cetirizine, ranitidine, and montelukast), those randomized to supplementation with high-dose vitamin D3 (4,000 IU/d) had a trend toward lower total symptom severity scores at the end of the trial (significant reduction in hive body distribution and duration, improved pruritus, and improved sleep quality) compared with patients randomized to low-dose vitamin D3 supplements ²¹.Although baseline total Urticaria Symptom Severity (USS) scores were similar between the 2 groups, and each group had a 33% reduction in total USS scores on triple-drug therapy at 1 week follow-up, by 12 week follow-up, the high-dose vitamin D3 group showed an additional 40% decrease in total USS scores that was not seen in the low-dose group. Despite an increase in levels of serum 25-hydroxyvitamin D with high-dose vitamin D3 supplementation, there was no corresponding association between 25-hydroxyvitamin D levels and USS scores. No adverse events were reported, and medication use in both groups remained similar ²².
• Autologous whole blood injection. Autologous whole blood injection may be an alternative to treat adults with refractory chronic urticaria. In a study of 19 patients in which autologous whole blood injection was performed on a weekly basis for 8 weeks, a significant improvement was seen in urticaria symptoms and quality-of-life scores ²³.

In a recent study published in the Journal of Allergy and Clinical Immunology: In Practice ²⁴, found many of the children treated in the clinic responded to one of the two antihistamines. However, 35% had hives resistant to even high doses of the antihistamines. The doctors found that those with hives resistant to antihistamines (hydroxyzine or cetirizine) were generally older children, with an average age of 12 years. The presence of autoimmune antibodies were not associated with a lack of benefit from antihistamines. All children had their hives completely suppressed by either the antihistamines or within days to a few weeks from the addition of cyclosporine. The average duration for continued use of cyclosporine was five months. When cyclosporine was stopped, most of the children remained free of hives. Only five of the 16 treated with cyclosporine had their hives return after an average of six months. No adverse effects were seen from either the antihistamines or cyclosporine.

Home remedies for chronic urticaria

Chronic hives can go on for months and years. They can interfere with sleep, work and other activities. The following precautions may help prevent or soothe the recurring skin reactions of chronic hives:

• Wear loose, light clothing.
• Avoid scratching or using harsh soaps.
• Soothe the affected area with a bath, fan, cool cloth, lotion or anti-itch cream.
• Keep a diary of when and where hives occur, what you were doing, what you were eating, and so on. This may help you and your doctor identify triggers.
• Avoid known triggers.
• Apply sunscreen before going outside.

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