Pressure urticaria is a rare entity of physical urticaria, a subset of chronic urticaria, which presents with erythematous swelling at sites of pressure. Chronic urticaria is diagnosed when patients have ongoing urticaria for more than 6 weeks. An inciting event or etiology is usually not identified for patients with chronic urticaria, and the term chronic idiopathic urticaria (CIU) is often used. A proportion of patients diagnosed with chronic urticaria have physical urticaria, which is urticaria caused by a physical stimulus, such as mechanical (friction, vibration, pressure), thermal, or electromagnetic waves.
Pressure urticaria may occur immediately (within minutes) or more commonly 4-6 hours after a pressure stimulus. For this reason, the term delayed pressure urticaria (DPU) is typically used. It appears as an erythematous, cutaneous, and often subcutaneous edema. The reaction may last up to 72 hours and can be associated with pruritus, burning, and pain. Pressure sites, including the hands, feet, trunk, buttocks, and legs, are most commonly affected. Lesions can be induced by a variety of stimuli, including standing, walking, wearing of tight clothes, and sitting or leaning on a hard surface. See the image below.
Delayed pressure urticaria. Image courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/reactions/pressure2.jpg).
For further information on urticaria, see Contact Syndrome Urticaria, Dermographism Urticaria, and Solar Urticaria. For patient education resources, see the Allergy Center and the Skin, Hair, and Nails Center, as well as Hives and Angioedema.
The pathogenesis of delayed pressure urticaria (DPU) is relatively unknown. Although the trigger stimulus is typically identified, no allergen has been established. The general pathogenesis of urticaria (hives) can be mediated immunologically or nonimmunologically, usually antibodies against IgE molecules are involved. IgE molecules attach to mast cells. When an antibody or autoantibody attaches to the antigen-binding site of the IgE molecule, a bridge is formed between two or more IgE molecules. This induces mast cell degranulation, releasing multiple proinflammatory mediators, including histamine. In chronic idiopathic urticaria (CIU), the mast cells are inappropriately activated.
In DPU, mast cells and histamine are believed to play a role in the disease pathogenesis, as injections of a mast cell degranulator, compound 48/80, lead to the formation of wheals in patients with DPU both 15 minutes after injection, as well as at 6-8 hours after injection. Injections in patients with chronic urticaria but without DPU produce wheals at 15 minutes that diminish over time. Histamine injections in both patients lead to initial wheal formation with no late phase reaction.
Histamine levels are increased in the lesional skin, while intracellular histamine levels are decreased in peripheral white blood cells. There is also an increased stimulation of histamine release. Despite these findings, histamine is unlikely to be the sole mediator in pressure urticaria. This is further demonstrated in the inconsistent effectiveness of antihistamine treatment in pressure urticaria.
Other mediators are believed to be involved. This includes eosinophils (as suggested by the presence of eosinophilia), eosinophil cationic protein (ECP), and eosinophil cationic factor (ECF) found in biopsy specimens from select patients with DPU, particularly those with bullous DPU. In addition, elevated concentrations of interleukin (IL)–1a, IL-5, and IL-6; tumor necrosis factor (TNF)–alpha; and leukotrienes have also been found in lesional skin of pressure urticaria patients.[10, 11, 12] Vascular endothelial growth factor has also been found to be elevated in patients with DPU. Abnormalities in platelets and fibrin or fibrinolysis have also been investigated.[14, 15] Systemic inflammation has also been suggested with elevations seen in C-reactive protein (CRP) and sCD40L, a platelet activator.[16, 17]
Pressure stimuli may include the following:
Occasionally, delayed pressure urticaria (DPU) is aggravated by heat, aspirin, or menstruation. Exacerbation of the condition during medical procedures is a reasonable possibility; urticaria flares following endoscopy have been described.
Delayed pressure urticaria (DPU) is generally considered a rare entity; however, this may be due to the fact that it is not consistently recognized. One study of 2310 patients with urticaria seen over 32 years found the prevalence of DPU to be 2%.
The peak age of onset of DPU is in the 20s and 30s (range, 5-63 y). DPU is slightly more common in men than in women.
Delayed pressure urticaria (DPU) is a chronic disease that can last for years (mean, 9 y; range, 1-40 y). One study reported that 28% and 48% of patients with DPU were free of lesions after 5 and 10 years, respectively. The morbidity of DPU varies, depending on the severity and the response to treatment. In some patients, this condition can be disabling, especially in patients who perform manual labor.
Quality-of-life (QOL) tools have demonstrated that patients with urticaria can show impairments in QOL scores similar to those seen in patients with chronic dermatoses such as psoriasis and atopic eczema. QOL scores were lowest for energy, social isolation, emotional reaction, and sleep disturbance.
The clinical manifestations of delayed pressure urticaria (DPU) differ from those typical of most types of urticaria. Onset is typically delayed, most commonly occurring 4 hours after the pressure stimulus. Less commonly, wheals due to pressure develop within minutes, in which case they may be confused with dermatographism. The lesions of DPU can persist for several hours and sometimes for as long as 72 hours, unlike those in typical urticaria, which resolve within 24 hours.
The physical findings in DPU include wheals, typically involving the palms, soles, legs, and waist. DPU lesions may also involve the genitals. The wheals, which appear as deep dermal and subcutaneous swellings, often resemble angioedema more than they do typical urticaria. Typical urticaria may also be present as a result of coexisting chronic idiopathic urticaria (CIU) or some other chronic physical urticaria.
The lesions may be pruritic, painful, or burning. They can occur on any cutaneous surface and may mimic angioedema. With severe episodes, patients may experience fever, malaise, fatigue, chills, headache, and generalized arthralgias. Affected areas can be refractory to the development of new lesions for 1-2 days.
As many as 60% of individuals with DPU have concomitant chronic idiopathic urticaria (CIU), immediate or delayed dermographism (dermatographism), or angioedema. In some reports, the incidence of DPU in patients with CIU varies considerably, ranging from 2% to 40%; other reports estimate the rate to be 2-4%.[1, 19, 22]
See the image below.
Delayed pressure urticaria. Image courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/reactions/pressure2.jpg).
An elevated white blood cell (WBC) count or neutrophilia may be present.[23, 24] Complement levels are normal.
Some patients with delayed pressure urticaria (DPU) also have concomitant chronic idiopathic urticaria (CIU). The following ancillary testing can be helpful in patients with CIU[25, 26] :
Pressure challenge testing (with the dermographometer or the suspended-weight method) may be performed for delayed pressure urticaria (DPU). Because therapy may influence test results, it is recommended that testing be performed at a time when therapy has been interrupted or stopped; however, some patients may have more severe disease that does not allow this. Repetitive testing can be used to assess response to therapy.
Multiple methods of applying measured amounts of pressure can be used to test for the development of DPU. A consensus conference review suggests using the following approaches :
The tests are most often applied to the shoulders, upper back, posterior thighs, or volar forearm. Pressure provocation tests should be read at 6 hours. Both the weight and the application time should be recorded. The duration of application is inversely related to the pressure applied; for example, wheals will take longer to develop with a lower pressure than with a higher pressure.
Several scoring systems are used to measure the severity of chronic urticaria, both in research settings and in clinical practice. A useful assessment tool was suggested by a European panel (see the Table below).
Table. Assessment Tool for Scoring Severity of Diseasea
The severity of delayed pressure urticaria (DPU) can vary throughout the day and from day to day. Overall disease activity is best assessed by having patients determine a severity score several times a day for several days before coming to their appointments.
The histologic features of delayed pressure urticaria (DPU) lesions are variable, often depending on the age of the lesion. Biopsy within hours demonstrates moderate-to-heavy infiltration of eosinophils with neutrophils and lymphocytes in a perivascular and interstitial pattern in the dermis and subcutaneous fat. Degranulated mast cells may be noted. Biopsy of an older DPU lesion (>24 h) demonstrates eosinophils and lymphocytes.
No vessel-related changes (eg, leukocytoclasia or fibrinoid necrosis), such as those noted in urticarial vasculitis, are seen. Direct immunofluorescence test results are negative.
Several reports of bullous pressure urticaria have been reported, and histologic findings show spongiosis and intraepidermal bullae associated with an eosinophil-rich inflammatory infiltrate in the superficial and deep dermis.
Patients should attempt to limit pressure stimuli. A simple intervention is to broaden the handles on heavy items or straps on clothing to disperse the pressure over a larger area. However, avoidance is not easy and may not be helpful in patients with moderate-to-severe disease.
The results of pharmacologic treatment of delayed pressure urticaria (DPU) are somewhat disappointing. Second-generation antihistamines are first-line treatment. Second- and third-line agents include systemic corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, dapsone, sulfasalazine, montelukast, chloroquine, cyclosporine, intravenous immunoglobulin (IVIg), omalizumab, and anakinra.
Restrictions in activity depend on the severity of the disease. Consult a dermatologist or allergist for evaluation for other causes of urticaria.
Second-generation antihistamines can reduce the severity of symptoms of swelling frequency and severity and are helpful in controlling associated chronic idiopathic urticaria (CIU), but they may not control the symptoms completely. Some authors have used up to four times the recommended dose of nonsedating antihistamines to achieve control.
NSAIDs produce variable responses. As treatment, they may be suboptimal because they, along with aspirin, may worsen urticaria and angioedema. Indomethacin has not demonstrated efficacy in the treatment of delayed pressure urticaria (DPU).
Steroids are best restricted for recalcitrant and severe DPU. Prednisone has some clinical efficacy, but long-term therapy is problematic because of its many adverse effects. One study of a small group of patients found high-potency topical steroids to be efficacious for reducing edema, erythema, and pruritus associated with DPU lesions. Patients who see improvement with systemic steroid therapy often relapse when these agents are discontinued. The adverse effects of steroids must also be considered and managed. Methotrexate has been used successfully in steroid reduction in a few patients with steroid-dependent DPU.
Omalizumab, a recombinant DNA monoclonal antibody that binds to IgE, is showing beneficial results in CIU, owing to its ability to decrease mast cell degranulation. Three phase 3 clinical trials, ASTERIA I, ASTERIA II, and GLACIA, involving over 900 patients with chronic spontaneous urticaria showed the benefits of omalizumab. A phase 3, multicenter study has shown omalizumab to decreased itchiness and hives and increase quality of life (QOL) in patients with CIU or chronic spontaneous urticaria, who had been refractory to antihistamine therapy. Patients, including those with DPU, who initially had a positive response to omalizumab, and then relapsed after stopping treatment, achieved remission after restarting omalizumab. Multiple case reports have reported the benefit of omalizumab treatment in patients with DPU. This potentially could be excellent treatment for DPU, although it is currently only US Food and Drug Administration (FDA) approved for chronic spontaneous urticaria.
Other therapeutic agents that have been tried include colchicine, dapsone, sulfasalazine, and montelukast.[34, 35] Colchicine has been largely ineffective as a therapy. Dapsone has demonstrated beneficial results persisting after treatment in a small study. A 2015 case series showed that in 17 patient treated with sulfasalazine, 11 had complete or near complete resolution and four had a partial response. Reports from small studies have found leukotriene antagonists, alone or in combination, to be efficacious for the treatment of DPU ; other forms of chronic urticaria have not demonstrated similar responses to this treatment. Case reports have demonstrated successful treatment with chloroquine, cyclosporine, IVIg, tricyclic antidepressants, selective serotonin reuptake inhibitors, and anakinra have each been used in a small number of patients with relative success.[38, 39, 40, 41, 42, 43]
Combination therapy may decrease disease activity. Adjunctive agents that reportedly have been successfully used in this context include leukotriene antagonists (eg, montelukast, zafirlukast) and H2-receptor antagonists (eg, famotidine, ranitidine).
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Agents used in the management of pressure urticaria include antihistamines, leukotriene antagonists, corticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs). The benefit of omalizumab has been established in chronic spontaneous urticaria and shows potential for patients with delayed pressure urticaria (DPU). There are many experimental drugs being used.
Clinical Context: Levocetirizine is an H1-receptor antagonist and an active enantiomer of cetirizine. Peak plasma levels are reached within 1 hour, and the half-life is approximately 8 hours. Levocetirizine is available as a 5-mg breakable (scored) tablet and a 0.5 mg/mL oral solution. It is indicated for uncomplicated skin manifestations of chronic idiopathic urticaria (CIU).
Clinical Context: Fexofenadine is a nonsedating second-generation medication that has fewer adverse effects than first-generation medications. It competes with histamine for H1 receptors in the gastrointestinal (GI) tract, blood vessels, and the respiratory tract, reducing hypersensitivity reactions. Fexofenadine does not sedate. It is available in once-daily and twice-daily preparations.
Clinical Context: Loratadine selectively inhibits peripheral histamine H1 receptors.
Clinical Context: Desloratadine is a long-acting tricyclic histamine antagonist that is selective for H1 receptors. It is a major metabolite of loratadine, which, after ingestion, is extensively metabolized to the active metabolite 3-hydroxydesloratadine.
Clinical Context: Cetirizine selectively inhibits H1 receptor sites in blood vessels, the GI tract, and the respiratory tract, thereby inhibiting the physiologic effects that histamine normally induces at H1 receptor sites. Once-daily dosing is convenient; bedtime dosing may be useful if sedation is a problem.
Antihistamines may be useful in helping control symptoms of chronic urticaria, which frequently coexists with delayed pressure urticaria (DPU). Second-generation antihistamines, also known as less-sedating or low-sedation antihistamines, produce less sedation than traditional H1 blockers because they are less lipid-soluble and only cross the blood-brain barrier in small amounts. They also have longer half-lives, allowing less frequent dosing. Many H1 antagonists are metabolized through the cytochrome P-450 system. Important exceptions include cetirizine, levocetirizine, and fexofenadine.
Clinical Context: Diphenhydramine is a first-generation antihistamine with anticholinergic effects. It binds to H1 receptors in the central nervous system (CNS) and the body, competitively blocking histamine from binding to these receptors.
Diphenhydramine is employed for symptomatic relief of pruritus caused by release of histamine in inflammatory reactions. It has significant antimuscarinic activity and penetrates the CNS and thus has a pronounced tendency to induce sedation. Approximately half of those treated with conventional doses experience some degree of somnolence. A small percentage of children paradoxically respond to diphenhydramine with agitation.
Clinical Context: Hydroxyzine antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the CNS.
First-generation antihistamines compete with histamine at the tissue-receptor level, preventing it from carrying out its mediator functions in urticaria.
Clinical Context: Famotidine is an H2 antagonist that, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.
Clinical Context: Ranitidine is a second-generation agent that is effective for the treatment of urticaria. It is tolerated very well, with a rate of sedation that is not significantly different from that seen with placebo.
Clinical Context: This agent competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations.
Clinical Context: This agent inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.
H2 antagonist therapy can be used as an adjunct to H1 antagonist therapy.
Clinical Context: Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.
Clinical Context: This glucosteroid occurs naturally and synthetically. It is used for both acute and chronic asthma. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.
Because of their anti-inflammatory properties, corticosteroids have been used in the management of pressure urticaria, with variable success.
Clinical Context: Omalizumab is a recombinant humanized monoclonal antibody administered by subcutaneous injection every 4 weeks. It selectively binds to IgE and inhibits binding to IgE receptors on the surface of mast cells and basophils. It is indicated for chronic idiopathic urticaria in adults and children aged 12 years or older who remain symptomatic despite anti-H1 antihistamine treatment.
Monoclonal antibodies directed to immunoglobulin E (IgE) binding may reduce the release of mediators that provoke an allergic response. These agents may be considered when H 1 -receptor antagonists are ineffective.
Clinical Context: Ibuprofen is an NSAID with analgesic, anti-inflammatory, and antipyretic properties. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Clinical Context: Naproxen inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.
NSAIDs are the medications most commonly used to control mild to moderate pain and to decrease inflammation. Sulfasalazine, steroids, and immunosuppressive agents are sometimes used, with varying degrees of success. NSAIDs can also be a nonimmunologic trigger of mast cell degranulation and subsequent urticaria.
Clinical Context: Doxepin is a tricyclic antidepressant that has potent H1-blocking activity, which makes it quite useful for urticaria. However, doxepin has very potent sedative and anticholinergic effects. It can be quite effective if given at bedtime because its sedative effects can make it easier for patients with pruritus to sleep.
Agents in this class that antagonize the H1 receptor preventing histamine from causing urticaria. The tricyclic antidepressant doxepin is used in urticaria for its sedative and antihistaminic properties. Oral doxepin may be considered if oral antihistamines are not helpful.
Clinical Context: Leukotriene inhibitors can be a helpful addition to therapy in patients with asthma and allergic rhinitis that are not well controlled with H1-receptor blockers and inhaled corticosteroids.
Clinical Context: Zafirlukast inhibits effects mediated by leukotriene receptors, the activity of which has been associated with airway edema, smooth muscle contraction, and cellular activity associated with symptoms.
Leukotriene antagonists, alone or in combination, have been found to be efficacious for treating delayed pressure urticaria (DPU). Other forms of chronic urticaria have not demonstrated similar responses to this treatment.
Clinical Context: Sulfasalazine decreases the inflammatory response and systemically inhibits prostaglandin synthesis.
These agents have anti-inflammatory effects.
Clinical Context: Clobetasol propionate is a class I superpotent topical steroid; it suppresses mitosis and increases synthesis of proteins that decrease inflammation and cause vasoconstriction. Clobetasol decreases inflammation by stabilizing lysosomal membranes, inhibiting PMN leukocytes and mast cell degranulation.
Some small studies have shown topical corticosteroids to be efficacious in reducing the size of pressure urticaria lesions, as well as the erythema and pruritus associated with them.
Score Wheals Pruritus 0 None None 1 Mild (<20 wheals/24 h) Mild 2 Moderate (21-50 wheals/24 h) Moderate 3 Intense (>50 wheals/24 h) or large confluent areas Intense aScore = wheal score (0-3) + pruritus score (0-3); thus, the overall score for severity ranges from 0 to 6.