Methotrexate-responsive chronic idiopathic urticaria: a report of two cases.

Chronic idiopathic urticaria (CIU) may be severe and refractory to standard therapies. We describe two patients with CIU, neither of whom had detectable autoantibodies, in whom control of the disease was achieved with methotrexate.

Unusual urticarias.

Typical urticarial lesions are transient cutaneous swellings of sudden onset, often itchy, persisting for less than 24 hours and resolving to leave normal appearing skin. Angioedema lesions are similar subcutaneous lesions. Atypical urticarias persist for longer than 24 hours, may be painful and bruised in appearance and accompanied with severe systemic symptoms. Conditions where prolonged weals are present include delayed pressure urticaria and urticarial vasculitis. These conditions do not respond well to antihistamine therapy. In delayed pressure urticaria, weals appear after a delay of hours at sites of sustained pressure on the skin and occur in association with ordinary chronic 'idiopathic' urticaria. Weals of urticarial vasculitis show histological features of venulitis, and can be accompanied by arthralgia and abdominal pain. Rarely, the condition is due to infective or autoimmune disease. Urticarial diseases, sometimes with features of urticarial vasculitis, and with associated systemic features include Schnitzler's Syndrome, Still's disease and Muckle-Wells syndrome. The latter syndrome is linked with chromosome 1q44, as is autosomal dominant cold urticaria, an unusual physical urticaria. Persistent cholinergic erythema, a variant of cholinergic urticaria, has been mistaken for a drug eruption or cutaneous mastocytosis. Rarely, food and exercise induced urticaria and anaphylaxis occur when exercise follows a specific food or any meal within a few hours. The early stages of inflammatory disease may be mistaken for urticaria and angioedema, but lesions usually persist for longer than 48 hours and are accompanied by epidermal changes.

The clinical presentations of urticaria.

Urticaria is a common skin condition. Although an episode may be mild and last only a few days, chronic urticaria can significantly affect the quality of life. The condition is frequently misunderstood by patients who believe the condition is always the result of an allergy and is dangerous.

Schnitzler's syndrome: no evidence for autoimmune basis in two patients.

We report two cases of Schnitzler's syndrome in which anti-interleukin-1alpha autoantibodies and functional autoantibodies against the high affinity IgE receptor (FcepsilonRIalpha) or against IgE were absent. One patient responded well to TL-01 phototherapy, a treatment which may be considered in patients with Schnitzler's syndrome if, as is usually the case, they are unresponsive to antihistamine therapy.

Chronic idiopathic urticaria: comparison of the clinical features of patients with and without anti-FcepsilonRI or anti-IgE autoantibodies.

BACKGROUND: Previous studies defining the clinical features of patients with chronic idiopathic urticaria (CIU) were performed before the identification of functional autoantibodies against FcepsilonRI and/or IgE, now known to be present in approximately 30% of patients with CIU. OBJECTIVE: Our purpose was to determine whether there are differences between patients with and those without autoantibodies in the clinical features or severity of CIU. METHODS: The clinical features of 107 patients with CIU were evaluated prospectively. Patients were identified as having functional autoantibodies on the basis of the serum-evoked histamine release in vitro from the basophils of 2 healthy donors. RESULTS: Patients with autoantibodies (31%) had more wheals (P = .005), a wider distribution of wheals (P = .009), higher itch scores for the most severe episodes of itching (P = .002), more systemic symptoms (P = .03), and lower serum IgE levels (P < .0005) than patients without autoantibodies. CONCLUSION: The presence of autoantibodies indicates a subset of patients with more severe CIU.

Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FcepsilonRI or anti-IgE autoantibodies.

BACKGROUND: Previous studies defining the histopathologic features of patients with chronic idiopathic urticaria (CIU) were performed on wheals of uncertain duration and before the identification of functional autoantibodies against FcepsilonRI and/or IgE, now known to be present in approximately 30% of patients with CIU. OBJECTIVE: We sought to determine the timing of the inflammatory infiltrate in the wheals of patients with CIU and to detect differences between patients with and without autoantibodies. METHODS: Immunohistochemistry was used to identify neutrophils (neutrophil elastase), T lymphocytes (CD3), and activated eosinophils (EG2) in biopsy specimens from uninvolved skin and wheals present for less than 4 hours and greater than 12 hours in 22 patients with CIU, as well as in biopsy specimens from the skin of 12 healthy control subjects. Patients were identified as having functional autoantibodies on the basis of their serum-evoked histamine release in vitro from the basophils of 2 healthy donors. RESULTS: EG2(+), neutrophil elastase+, and, to a lesser extent, CD3(+) cells were found in greater numbers in wheals undergoing biopsy at less than 4 and greater than 12 hours than in uninvolved skin (P <.05). Patients without autoantibodies (n = 12) had significantly more EG2(+) cells in wheals of greater than 12 hours' duration than patients with autoantibodies (n = 10; P =.02). There was no other difference between patients with and without autoantibodies in the cutaneous cellular infiltrate. CONCLUSION: Neutrophil and eosinophil accumulation occurs early in the evolution of a wheal in patients with CIU, but eosinophil activation may occur later or be more persistent in patients without autoantibodies.

Anti-Fc(episilon)RI auto antibodies and basophil histamine releasability in chronic idiopathic urticaria.

BACKGROUND: Circulating functional autoantibodies to the high-affinity IgE receptor (Fc(epsilon)RI) or to IgE have been found in approximately one third of patients with chronic idiopathic urticaria (CIU). OBJECTIVE: We sought to compare basophil histamine release and basophil numbers in patients with CIU with and without autoantibodies. METHODS: Basophil histamine release to the anti-Fc(epsilon)RI mAb 22E7, anti-IgE, and formyl-methionyl-leucyl-phenylalanine (fMLP); basophil numbers; and total cellular histamine were measured in 26 patients with CIU and 18 healthy control subjects. Twelve patients were classified as having functional anti-Fc(epsilon)RI and/or anti-IgE autoantibodies on the basis of their serum-evoked histamine release from the basophils of 2 healthy donors. RESULTS: 22E7 and anti-IgE, but not fMLP, released less histamine from basophils of patients with CIU than from those of control subjects. Mean+/-SEM maximum histamine release to 22E7 from basophils of control subjects and patients with CIU with and without autoantibodies was 38.5%+/-5.0%, 17.9%+/-6.0% (P =.01), and 1.0%+/-0.3% (P <.0001), respectively. Similar results were obtained with anti-IgE, which is dependent on and cross-links cell bound IgE, and 22E7, which directly cross-links the IgE receptor. The mean+/-SEM basophil counts for control subjects and patients with CIU without and with autoantibodies were 52+/-7, 34+/-9 (P =.04), and 5+/-1 (P <.0001) x 10(6) cells/L, respectively, and similar changes were found in measurements of total cellular histamine. CONCLUSION: Patients with autoantibodies have both markedly reduced basophil numbers and basophil histamine release to factors acting through Fc(epsilon)RI, which indicates either a residual pool of functionally distinct basophils or may be a consequence of desensitization of the Fc(epsilon)RI pathway.

Intravenous immunoglobulin in autoimmune chronic urticaria.

Histamine releasing autoantibodies play a central role in the pathogenesis of chronic urticaria (CU) in approximately 30% of affected patients. We investigated the therapeutic effect of high-dose intravenous immunoglobulin (IVIG) on disease activity in patients with severe CU of autoimmune aetiology. Autoimmune urticaria was diagnosed by the development of a weal-and-flare reaction to the intradermal injection of autologous serum and by serum-induced histamine release from the basophil leucocytes of healthy donors in vitro. Ten patients with severe, autoimmune CU, poorly responsive to conventional treatment, were treated with IVIG 0.4 g/kg per day for 5 days. The outcome on cutaneous wealing and itch was monitored using urticaria activity scores, visual analogue scales and autologous intradermal serum tests. Clinical benefit was noted in nine of 10 patients: three patients continue in prolonged complete remissions (3 years follow-up), two had temporary complete remissions, and symptoms in four patients improved subsequent to treatment. There was significant improvement in the urticaria activity scores and visual analogue scores at 2 (P < 0.01) and 6 weeks (P < 0.01) post-IVIG compared with the baseline values (Wilcoxon matched pairs). The diminution in urticarial activity in the majority of patients corresponded with a reduced weal-and-flare response to the intradermal injection of autologous post-treatment serum compared with the pretreatment serum. Minor side-effects were common, but there were no serious or long-term adverse effects. IVIG represents a novel therapeutic option in selected patients with recalcitrant CU associated with histamine releasing autoantibodies.

The pathogenesis of urticaria.

The underlying pathophysiology of chronic urticaria is mast cell activation, with release of histamine and other mast cell mediators. A weal producing factor has been identified in the serum of 60% of patients with chronic idiopathic urticaria. In half of these patients there is evidence for functional autoantibodies against the high affinity IgE receptor or IgE, or both. These autoantibodies release histamine from basophils and mast cells. It is therefore likely that there is an autoimmune basis for up to 30% of patients with idiopathic urticaria. In the other half of patients whose serum causes weals, the factor releases histamine from mast cells only and is as yet unidentified. So far no clinical difference has been associated with presence/absence or type of weal producing factor. Exacerbating factors in chronic urticaria such as aspirin, food additives, febrile illness and psychological stress should be identified and avoided. Treatment is symptomatic with the low sedation antihistamines. In the most severe cases not responding to conventional therapy and which may have the weal producing factor, treatments with non specific immune therapy such as cyclosporin, and intravenous gammaglobulin and also plasmapheresis have been promising.

Angiotensin-converting enzyme (ACE) inhibitors and angio-oedema.

Angiotensin-converting enzyme inhibitors (ACEIs) are used increasingly for the treatment of hypertension and chronic heart failure, and they reduce mortality when given after myocardial infarction. Of the patients prescribed these drugs 0.1-0.7% develop angio-oedema, but the association is not widely recognized. In 60% of cases the onset occurs during the first week of treatment; however, it may be considerably delayed. Angio-oedema nearly always occurs on the head and neck, frequently involving the mouth, tongue, pharynx and larynx. The course is unpredictable, and attacks vary in severity from mild to fatal from laryngeal obstruction. Severe ACEI-induced angio-oedema may require emergency treatment with adrenalin and early intubation. The drug should be withdrawn in any patient who presents with ACEI-induced angio-oedema, and treatment continued with an appropriate drug of a different class. Therapy with ACEIs is contraindicated in patients with a prior history of idiopathic angio-oedema, or in patients with hereditary or acquired C1 esterase inhibitor deficiency.

Vitamin B-12 deficiency and malabsorption are highly prevalent in rural Mexican communities.

Vitamin B-12 status of rural Mexicans was evaluated in two studies, 6 y apart. In the first, a single blood sample was collected from children and adults, including pregnant and lactating women. Prevalence of deficient plasma vitamin B-12 values ranged from 19% to 41% among groups, but plasma folate status was normal in all individuals. Breast milk vitamin B-12 concentration was low in 62% of samples. The second study was conducted in 219 children aged 18-36 mo in five communities, whose prevalence of deficient and low plasma vitamin B-12 concentrations, respectively, was 8% and 33% on entry, 3% and 22% 6 mo later, and 7% and 29% 12 mo later. Prevalence of low holotranscobalamin II concentrations, indicating malabsorption of the vitamin, averaged 18-40% across the three same periods. Both vitamin B-12 status indicators differed significantly between communities. The widespread vitamin B-12 deficiency was probably caused by malabsorption, perhaps exacerbated by low dietary intake and, for young children, maternal depletion of the vitamin.

Urticarial vasculitis.

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The incidence of vasculitis in patients with apparent urticaria is between 2% and 20%. The diagnosis is suggested clinically by more persistent (lasting > 24 hours) and more symptomatic weals than in ordinary urticaria and by the presence of residual bruising. In addition to the skin the musculoskeletal, respiratory, renal and gastrointestinal systems may be involved in the disease, which is probably an immune complex mediated process. Urticarial vasculitis is most commonly an acquired idiopathic phenomenon but may occur in association with other disorders most often systemic lupus erythematosus, Sjögren's syndrome and serum sickness. In this article we review the background, histopathology, clinical features, extracutaneous manifestations, pathogenesis, aetiology, associated diseases, investigation, treatment, course and prognosis of urticarial vasculitis.

The effects of topical corticosteroids on delayed pressure urticaria.

Six patients with delayed pressure urticaria (DPU) applied clobetasol propionate (0.05%) ointment or its base to predetermined test sites on the right and left thigh as part of a randomized, double-blind study. A pressure challenge was administered to each test site at the initial visit and repeated after 3 days and 6 weeks of treatment and at between 4 and 8 weeks after treatment. The areas of pressure-induced weals were measured 6 h after each challenge. At the 6-week visit, a 4-mm punch biopsy was taken from pressure-challenged skin on each test site. Sections were stained for mast cells and immunohistochemical labelling was used to demonstrate neutrophils (neutrophil elastase), eosinophils (eosinophil cationic protein), monocytes/macrophages (EBM 11), cells expressing the beta-2 integrins (CD11/18) and the vascular adhesion molecules, E selectin and intercellular adhesion molecule-1 (ICAM-1). In the steroid-treated sites, there was a significant decrease (P < 0.05, Wilcoxon's matched-pairs test) in the size of the pressure weals compared with baseline at 3 days, 6 weeks and at follow-up. Demonstrable mast cells were significantly decreased (P = 0.059) in the pressure-challenged areas in the steroid-treated sites compared with the base-treated sites. The histological response to pressure was minimal in both sites perhaps demonstrating an active pharmacological effect of the ointment base. In conclusion, the application of potent topical steroids significantly reduced the clinical response to pressure in patients with DPU, possibly through a reduction in mast cells.

Adhesion molecule expression and the inflammatory cell infiltrate in delayed pressure urticaria.

We have investigated the kinetics of the leucocyte infiltrate in delayed pressure urticaria (DPU) in relation to the in vivo expression of the cytokine-regulated cell surface adhesion molecules, E-selectin (endothelial adhesion molecule-1, ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1). Immunohistochemical analysis was performed on biopsies taken from unchallenged skin, and at 0, 2, 6, 24, 48 and 120 h after weighted rods had been applied to 13 patients with DPU. There was moderate to marked upregulation of E-selectin at 6 and 24 h after application of pressure. At 24 h, more patients showed expression of VCAM-1 on perivascular cells than before pressure. Moderate expression of ICAM-1 was present in some biopsies from both unchallenged and pressure-challenged skin, but there was no clear trend. In DPU, there was a significant increase in the neutrophil count at 2 h after a pressure challenge, with further increases at 6 and 24 h. The median cell counts per high-power field of eosinophils and monocyte/macrophages increased significantly at 24 h after pressure. Biopsies from four normal controls subjected to an identical pressure challenge showed no detectable changes in adhesion molecule expression or in the cell infiltrate. The findings in four patients with chronic idiopathic urticaria not associated with DPU were qualitatively similar to (but intermediate in severity between) the findings in DPU weals at 6 and 24 h. These results suggest that vascular endothelial activation is an early response to pressure challenge in DPU, and is also present in chronic idiopathic urticaria.(ABSTRACT TRUNCATED AT 250 WORDS)

Iron, vitamin B-12 and folate status in Mexico: associated factors in men and women and during pregnancy and lactation.

To determine the prevalence and causes of anemia in rural Mexico, blood samples and longitudinal dietary data were collected from 187 women, some pregnant and then lactating, and from 72 men. Blood was used to measure anemia, mean cell volume, and plasma ferritin, folate and vitamin B-12. Anemia was found in 33% of the men, 54% of nonpregnant, nonlactating women, 35% of pregnant women and 41% of lactating women, and varied by season. Low iron stores (ferritin) accompanied anemia in only 8% of men compared with 38-67% of women. Low meat intake and poor dietary iron bioavailability were associated with anemia in women. There were no cases of low plasma folate. Low plasma vitamin B-12 was common in all groups, and the incidence increased from 15% at 7 mo of pregnancy to 30% at 7 mo of lactation. Vitamin B-12 was lower in the plasma and milk of anemic lactating women than in plasma and milk of non-anemic lactating women and was classified as deficient in 62% of breast milk samples.

Diagnosis and incidence of delayed pressure urticaria in patients with chronic urticaria.

BACKGROUND: The incidence of delayed pressure urticaria (DPU) may have been underestimated, particularly in patients with widespread wheals of concurrent idiopathic urticaria, because of difficulty in recognizing the association between pressure-related swellings and the preceding physical stimulus. Diagnostic tests for DPU have not been done routinely in studies of urticaria and have not been compared. OBJECTIVE: Our purpose was to establish the incidence of DPU and other physical urticarias in patients with chronic urticaria and to compare two reproducible pressure challenge tests. METHODS: One hundred thirty-five patients were tested for immediate dermographism, for DPU and, when indicated by the history, for cholinergic and/or cold urticaria. In patients with pressure-related symptoms, pressure challenge testing with a dermographometer (100 gm/mm2) was compared with a test that involves the application of 1.5 cm diameter weighted rods and more closely resembles a naturally occurring pressure stimulus. RESULTS: Physical urticarias were present in 96 patients (71%). Thirty patients (22%) had immediate dermographism, 50 (37%) had DPU, 15 (11%) had cholinergic urticaria, and 3 (2%) had cold urticaria. A 70-second pressure challenge with the dermographometer gave results comparable to the use of the weighted rods. CONCLUSION: DPU appears to be more common in chronic urticaria than previously reported and is present in some patients who do not report pressure-related wheals.

Cloning and characterization of a lignin peroxidase gene from the white-rot fungus Trametes versicolor.

Six putative lignin peroxidase (LIP) genes were isolated from a lambda EMBL3 phage library of the white-rot fungus, Trametes versicolor, using the Phanerochaete chrysosporium LIP cDNA CLG5 as the probe. Sequence analysis of one of the genes, VLG1, showed that its coding region is interrupted by six small introns (49-64 bp) and that it encodes a mature LIP protein (341 aa; Mr: 36,714) that is preceded by a 25 aa signal sequence. This protein has a relatively high degree of aa homology to the N-termini of the LIP proteins purified from T. versicolor and has an aa homology of 55-60% to the LIP proteins of P. chrysosporium, which is comparable to that found between P. chrysosporium and Phlebia radiata LIP proteins.