Chronic urticaria.

Chronic urticaria (CU) is a disturbing allergic condition of the skin. Although frequently benign, it may sometimes be a red flag sign of a serious internal disease. A multitude of etiologies have been implicated in the causation of CU, including physical, infective, vasculitic, psychological and idiopathic. An autoimmune basis of most of the 'idiopathic' forms is now hypothesized. Histamine released from mast cells is the major effector in pathogenesis and it is clinically characterized by wheals that have a tendency to recur. Laboratory investigations aimed at a specific etiology are not always conclusive, though may be suggestive of an underlying condition. A clinical search for associated systemic disease is strongly advocated under appropriate circumstances. The mainstay of treatment remains H1 antihistaminics. These may be combined with complementary pharmacopeia in the form of H2 blockers, doxepin, nifedipine and leukotriene inhibitors. More radical therapy in the form of immunoglobulins, plasmapheresis and cyclophosphamide may be required for recalcitrant cases. Autologous transfusion and alternative remedies like acupuncture have prospects for future. A stepwise management results in favorable outcomes. An update on CU based on our experience with patients at a tertiary care centre is presented.

Introduction

Urticaria (from the Latin word urtica, (to burn) or hives), are a kind of skin rash notable for dark red, raised, itchy bumps.[1] It affects 15-20% of the population once or more during a lifetime.[2] In around 30% patients of urticaria, attacks often recur for months or years. Chronic urticaria (CU) is defined by recurrent episodes occurring at least twice a week for 6 weeks.[3] Females are more commonly affected than males.[4] Establishing the cause of CU is difficult and at times almost impossible. This renders cause specific management difficult and frustration on part of the patient and the treating physician. Also, CU is associated with lower quality of life (QoL) levels.[56] Recent advances in our understanding of its pathogenesis include the finding of autoantibodies to mast cell receptors in nearly half of patients. This possibility of an autoimmune basis to chronic idiopathic urticaria (CIU) is now widely explored.[7] This review attempts to discuss the evidence-based pathogenesis and treatment options available, for CU.

Etiology

There is a long list of both external and internal causes of urticaria, and almost every observer is able to add to the list. A gist of the multitude of etiologies proposed is depicted in Figure 1.

Figure 1

Multiple etiologies of chronic urticaria shown under their broad headings

Physical factors

Physical urticaria accounts for about 15% of urticaria cases, and is triggered by exogenous mechanical stimuli.[8] A single patient may have more than one type. Below is a list of some types of physical urticaria and their causes.

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

Vibratory urticaria - Vibration

Autoimmune urticaria

In 1983, Leznoff et al,[9] suggested an autoimmune basis for the urticaria. This was after the observation that there was an association between thyroid disease and CIU. After that in 1988 Gruber et al,[10] detected functional anti-IgE antibodies and proposed that these could be the cause of urticarial wheals. It is now well-established that about 30-50% patients with CU have circulating functional auto antibodies against the high-affinity IgE receptor (FCeRIa) or against IgE. Also, urticaria has been associated with a number of autoimmune diseases.[11] A few of them are systemic lupus erythematosus, cryoglobulinemia, neoplasms, juvenile rheumatoid arthritis and autoimmune thyroid disease, including Graves disease.[9] Urticaria is a feature of Muckle-Wells syndrome (amyloidosis, nerve deafness and urticaria) and Schnitzler syndrome (fever, joint/bone pain, monoclonal gammopathy and urticaria).[1213]

Infections

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 virus, Streptococcus and Mycoplasma species, Helicobacter pylori, Mycobacterium tuberculosis, and herpes simplex virus.[1415] Fungal infections such as onychomycosis, tinea pedis and candida have been considered as possible associations.[16] CU has been associated with parasitic infestations such as strogyloidiasis, giardiasis and amoebiasis.[17]

Idiopathic/others

Most cases of CU are considered idiopathic. It has recently been accepted that autoimmunity plays a critical role in its pathogenesis in some of these patients.[1819] A few other offenders are listed as under:

Medications: Urticaria may be caused or exacerbated by a number of drugs. More common culprits include aspirin, other nonsteroidal anti-inflammatory drugs, opioids, ACE inhibitors, and alcohol. Aspirin may exacerbate CU in 6.7-67% of patients.[20] Other drugs implicated are alcohol, narcotics (codeine, morphine) and oral contraceptives.[21]

Contactants: Contact urticaria syndrome refers to the onset of urticaria within 30-60 minutes of contact with an inciting agent. The lesions may be localized or generalized. Precipitating factors include latex (especially in health care workers), plants, animals (eg, caterpillars, dander), medications, and food (eg, fish, garlic, onions, tomato).

Neurological factors: An Italian study[22] reported an association between CU and fibromyalgia. The authors proposed that CU is a consequence of fibromyalgia-neurogenic skin inflammation.

Stress: Psychological factors are reported to play a role in a number of patients. Zenon Brzoza et al in their study showed that the decline in dehydroepiandrosterone sulfate observed in CU is associated with psychological distress.[23] Depression may also cause or aggravate CU.[24]

Vasculitic

Tsunemi et al, reported a case of recurrent cutaneous eosinophilic vasculitis presenting as annular urticarial plaques.[25] Another confounding condition of interest is urticarial vasculitis,an eruption of erythematous wheals that clinically resemble urticaria but histologically show changes of leukocytoclastic vasculitis.[26] Patients with urticarial vasculitis present with an urticarial eruption, often accompanied by a painful or burning sensation. Lesions are generalized wheals or erythematous plaques, occasionally with central clearing, lasting for more than 24 hours in a fixed location (in contrast to urticaria, which resolves in minutes to hours or migrates continually).

Pseudoallergic

Some authors suggest that the etiology of disease for a portion of CIU patients is a pseudoallergy to food ingredients. The concept of pseudoallergic reactions was introduced in 1983 to describe responses to a food or chemical that mimicked the signs and symptoms of an allergic reaction but without isolation of specific IgE antibodies against the offending agent. Implicated agents include preservatives, sweeteners, artificial food dyes, aromatic volatile compounds in tomatoes, herbs, wine, salicylic acid, orange oil, alcohol and high dietary fats. 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. CU exacerbated by specific foods is fairly common, particularly among infants and children.[27] Frequently implicated food additives are tartrazine, other azo dyes including amaranth and sunset yellow, benzoic acid compounds, etc.

Pathophysiology

The mast cell is believed to be the major effector cell in most forms of urticaria, though other cell types may be involved. Degranulation of mast cells with release of histamine is central to the development of wheals and angioedema. Urticaria is due to a local increase in permeability of capillaries and venules. These changes are dependent on activation of the cutaneous mast cells, which contain a range of mediators predominantly histamine. The mast cells respond with a lowered threshold of releasability.[28] Vascular permeability in skin is produced by the interaction of both H1 and H2 histamine receptors. Activation of H1 receptors in the skin induces itching, flare, erythema, whealing and contraction of smooth muscle in respiratory and gastro-intestinal tract. Activation of H2 receptors contributes to erythema and whealing in the skin. Chronic autoimmune urticaria is caused by anti-FcåRI and less frequently, by anti-IgE autoantibodies that lead to mast cell and basophil activation. The postulated effector mechanisms for immunological and nonimmunological activation of mast cells is presented in Figure 2. A few preclinical investigations have demonstrated an upregulation of TNF-α in patients with CIU. This is in contrast to acute urticaria where TNF-α does not appear to play as important of a role in the inflammatory response. This may explain why patients with CIU do not typically respond to usual therapies for acute urticaria. It has been suggested that CIU is an immediate hypersensitivity phenomenon appearing immediately after exposure to an antigen, but the presence of a delayed inflammatory phase is nevertheless observed in this pathology.

Figure 2

Immunological and nonimmunological mechanisms of mast cell activation in urticaria

Clinical Features

CU is associated with diverse clinical presentations. It is chiefly characterized by the rapid appearance of wheals [Figure 3] and/or angioedema. A wheal consists of three typical features: (i) a central swelling of variable size;(ii) an associated itching or sometimes burning; and (iii) a fleeting duration of usually 1-24 h. Angioedema is defined as a sudden, pronounced swelling of the lower dermis and subcutis. It is sometimes painful and resolution is slower than for wheals (up to 72 h). In 40-50% of cases, urticaria is associated with angioedema.[29]

Figure 3

Wheals and erythematous papules in a patient with chronic urticaria

Lesions may appear anywhere on the body including scalp, palms and soles. Urticarial wheals are very itchy and patients tend to rub rather than scratch, hence excoriation marks are not seen. Headache, dizziness, hoarseness of voice, shortness of breath, nausea, vomiting and abdominal pain may occur as concomitant systemic manifestations of severe episodes of urticaria. Although patients with autoimmune antibodies have no distinctive diagnostic clinical features, the diagnosis of chronic autoimmune urticaria often can be suspected from a past or family history of autoimmune diseases, especially thyroiditis. A European panel on allergic diseases has suggested an assessment tool for scoring severity of disease in urticaria[30] presented in Table 1. Histopathological findings of urticarial wheals are usually nonspecific, comprising of vascular and lymphatic dilatation, edema and a variable perivascular cellular dermal infiltrate. The spectrum of cellular changes depends upon the age of the wheels and their underlying cause.[31] Histological examination in autoimmune urticaria shows pronounced eosinophil degranulation in older lesions compared with nonautoimmune cases.[32] A diagnostic algorithm based on recommendations of the British Society for Allergy and Clinical Immunology is illustrated in Figures 4 and 5.

Table 1

Severity score in urticaria

Figure 4

Algorithm for differential diagnosis and approach to chronic urticarial

Figure 5

Facial and palpebral angioedema

Investigations

In spite of extensive laboratory investigations, 50% cases of chronic urticaria remain idiopathic.[33] An elevated ESR suggests the possibility of an underlying systemic disease and eosinophilia should prompt a search for parasitic diseases. Screening test for thyroid function and antithyroid peroxidase and antithyroglobulin antibodies may be carried out in candidate patients. Positive autologous serum skin test (ASST)[34] suggests an underlying autoimmune mechanism. Confirmation is needed by in vitro testing of the patient's serum for the anti-FCeRIa or the anti-IgE auto antibodies. In vitro ‘the basophil histamine release assay[35] is currently the gold standard for detecting functional auto antibodies. A diagnosis of C1 esterase inhibitor deficiency should be suspected in the light of C4 hypocomplementemia and angioedema alone.[36]

Management

The treatment regimen should be tailored to the individual patient General measures include removal of any identifiable cause, explanation, information and reassurance. Avoidance of aspirin and other NSAIDs is recommended because these drugs aggravate chronic urticaria in about 30% of patients.[37] Treatment of underlying diseases, i.e. Hashimoto's thyroiditis, cryoglobulinemia and Helicobacter pylori when present is indicated. Ingestion of high quantities of salicylate in diet and its relation to urticaria has long been a matter of debate, although the same has been refuted by others. In one study, only 19% of patients reacted severely to challenge capsules containing food additives and salicylic acid.[38] Salicylates are the active ingredient in aspirin and are found in all plant matter to some extent (fruits, vegetables, herbal supplements, etc).

Pharmacotherapy

Primary treatment

The newer generation H1 antihistamines with less sedating and less cholinergic effects are preferred over the older generation H1 antihistamines as the initial choice of therapy.[39] In pregnancy, chlorpheniramine and diphenhydramine are the antihistaminics of choice for oral and parenteral route respectively.[40] Certain antihistamines have been proposed as preferred for particular subtypes of chronic urticaria, such as hydroxyzine for cholinergic urticaria and cyproheptadine for cold induced urticarial.[41] Second generation nonsedating (or less sedating) antihistamines like cetirizine, loratidine, fexofenadine, desloratadine, mizolastine, etc. also can be used. It is common to double or triple the dosage of nonsedating antihistamines if patients do not respond to standard dosage.[4243] The EAACI/GA2 LEN recommendation of using nonsedating H 1 antihistamines up to four fold above the recommended doses appears to be effective with mild sedation. It has been proposed to switch over from the current approach of adding another antihistamine to updosing the same antihistamine for desirable results.[44] If little response, then the tricyclic antidepressant doxepin,10-25 mg initially upto 75 mg at night[45] or H2 antihistamines[46] or mast cell stabilizers e.g., ketotifen[47] can be added. The doses of the common drugs used in the management of urticaria are depicted in Table 2.

Table 2

Common drugs and their dosages in chronic urticaria

Second line treatments

Short courses of systemic steroids (for example prednisone 0.3-0-5 mg/kg daily or methylprednisolone 16 mg daily to be tapered and stopped within 3-4 weeks) can be given in resistant cases of chronic urticaria, but long term therapy can not be proposed because of known adverse effects. Prolonged treatment of chronic urticaria with oral corticosteroids may be required in urticarial vasculitis.[48] If urticaria relapses after a short course of steroid therapy, and symptoms are not adequately controlled by H1 antihistamines, leukotriene-receptor antagonists could be tried . Leukotriene receptor antagonists, zafirlukast (20 mg twice daily) and montelukast (10 mg once daily) have been shown to have beneficial effect in treatment of chronic urticaria especially in cases which were aggravated by the NSAIDs and food additives.[49] Zileuton, a 5-lipooxygenase inhibitor, which inhibits leukotriene generation has been found to be effective in improving chronic urticaria. Rofecoxib,[50] a newer COX-2 inhibitor, has also been tried in treating patients with refractory CIU with good results.

Resistant/severe cases: Newer modalities

Cyclosporine[51] has been shown to be effective in severe unresponsive cases. High dose of intravenous immunoglobulin[52] has been found to be associated with some apparent benefits in the treatment of CU. Few authors have successfully shown that in patients with chronic autoimmune urticaria resistant to antihistamines, treatment with omalizumab (xolair) 150 mg to 300 mg once or twice a month depending upon weight and IgE levels (>=0.016mg/kg/IU mL-1 IgE per month) resulted in a significant reduction in the patients’ hives, reduced the need for additional medication to control symptoms, and improved patients’ QoL.[5354] Plasmapheresis[55] has been used to treat some patients with autoantibody positive severe CU. Oral tacrolimus, low-dose methotrexate, hydroxychloroquine, sulfasalazine and dapsone, which have immunomodulatory properties, are effective in the treatment of chronic urticaria. The primary indication of hydroxychloroquine, however, remains hypocomplementemic urticarial-vasculitis syndrome, in combination with systemic steroids. Sulfasalazine has been reported for the treatment of steroid-dependent CU. The usual starting dosage is 1 gm twice daily, leading to a maximum regular dosage of 4 gm daily.[56] Cyclophosphamide has also shown beneficial effect in treating severe autoimmune CU. Warfarin and tranexamic acid has been tried by some authors with variable results.[57] Phototherapy with ultraviolet light or photo chemotherapy has been used for treating CU, but the reported results have been inconclusive.[58] Nifedipine, a calcium channel blocking drug that possesses mast cell stabilizing properties as well can be started at a dosage of 5 mg thrice daily and increased up to 20 mg thrice daily.[59]

Alternative medicine

Few authors have suggested that acupuncture is effective in up to 90% of cases of CIU. In a case-control study, it was shown that the mean attack rate and mean duration of urticaria attack was reduced in the acupuncture treated patients and this effects was mostly seen a in the third week of treatment.[60]

Psychological therapy

A case has also been made for complementary psychological treatment of patients suffering from CIU, because of the high frequency of psychological symptoms. Particular attention is focused to hypnosis and relaxation techniques because of the improvement of the urticarial wheals reported in studies of cutaneous ability to react in subcutaneous injections of histamine.[61]

Future prospects

More selective immunotherapies offer promising prospects. The extracellular part of the ‘a’ subunit of FCeRIa or shorter peptide sequences containing the autoantibody epitopes could be used to bind to circulating FCeRIa auto antibodies, thereby inhibiting their attachment to receptors on mast cells or basophils. AST, a modified form of autologous whole blood therapy, has also been found to be fairly effective in CU.[5162]