Coagulation cascade and fibrinolysis in patients with multiple-drug allergy syndrome.

BACKGROUND: Previous studies have shown that patients with multiple-drug allergy syndrome (MDAS) frequently have positive autologous serum skin test results, similar to patients with chronic urticaria (CU). Recent investigations have found that patients with CU show signs of thrombin generation and activation of the tissue factor pathway of the coagulation cascade. OBJECTIVE: To study thrombin generation and fibrinolysis in patients with MDAS. METHODS: Nine patients with MDAS underwent autologous plasma skin testing (APST) and measurement of plasma prothrombin fragment F(1 + 2) and D-dimer levels. Furthermore, the basophil histamine-releasing activity of plasma from patients with MDAS was evaluated. Plasma samples from 74 healthy control subjects and 13 patients with CU were used as negative and positive controls, respectively. RESULTS: All 9 patients with MDAS had positive APST results, and 7 showed elevated plasma levels of fragment F(1 + 2). In patients with MDAS, the median F(1 + 2) level (339 pmol/L; interquartile range [IQR], 250-401 pmol/L) significantly exceeded that in healthy controls (159 pmol/L; IQR, 123-196 pmol/L) (P = .001) but did not significantly differ from that in controls with CU (292 pmol/L; IQR, 182-564 pmol/L; P = .38). Plasma D-dimer levels were normal in all the patients with MDAS and were significantly lower than in controls with CU (P = .009). Finally, the histamine-releasing activity of plasma from patients with MDAS was significantly increased and correlated with F(1+ 2) levels (r = 0.68; P = .04). CONCLUSION: Positive APST results and thrombin generation indicate a common physiopathologic background in MDAS and CU. The lower D-dimer levels suggest that fibrinolysis occurs less intensely in MDAS than in CU.     

Autoreactivity is highly prevalent in patients with multiple intolerances to NSAIDs.

BACKGROUND: A subset of drug-allergic patients show a marked propensity to react against several, chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis of such multiple drug reactions is unclear. Approximately 30% of patients with chronic idiopathic urticaria, a condition frequently characterized by autoreactivity on autologous serum skin test (ASST), experience flares of hives after taking chemically unrelated NSAIDs. OBJECTIVE: To detect whether a clinically unapparent autoreactivity may represent the nonspecific mechanism facilitating drug-induced histamine release in patients with a history of urticaria/angioedema induced by several, chemically unrelated NSAIDs. METHODS: Thirty-six adults with a history of acute NSAID-induced urticaria (22 with multiple NSAID sensitivity [MNS]; 14 with single NSAID sensitivity [SNS]; and 20 atopic controls without a history of drug allergy) underwent ASST. Sera from 14 MNS and 4 SNS subjects (all ASST-positive) underwent histamine release assay with basophils from normal donors. Sera from five MNS patients were tested on autologous basophils as well. RESULTS: Twenty of 22 (91%) MNS subjects versus 5 of 14 (36%) SNS subjects were positive on ASST (P < 0.01). No atopic control was ASST-positive. Sera from 4 of 14 (29%) MNS patients versus 0/4 SNS subjects (P = NS) induced significant histamine release from basophils of normal donors. The use of autologous basophils did not significantly change these results. CONCLUSION: Most patients with multiple NSAID intolerance and approximately one-third of those with single NSAID hypersensitivity are characterized by the presence of circulating histamine-releasing factors. Their nature is still unclear, but the fact that only a minority of sera from ASST+ subjects were able to induce histamine release from normal basophils in vitro suggests that these factors might not differ from those involved in most patients with chronic urticaria. These factors might play a relevant pathogenic role in NSAID-induced urticaria reactions.     

Plasma levels and skin-eosinophil-expression of vascular endothelial growth factor in patients with chronic urticaria

Background:  Although chronic urticaria (CU) is often regarded as autoimmune in nature, only less than 50% of sera from CU patients contain histamine-releasing autoantibodies. This suggests that other factors may contribute to its pathogenesis. We evaluated the possible involvement of vascular endothelial growth factor (VEGF), one of the major mediators of vascular permeability, in CU.
Methods:  Eighty consecutive adult patients with CU and 53 healthy subjects were studied. VEGF and prothrombin fragment F₁₊₂ were measured by enzyme immunoassays. Autologous plasma skin test (APST) was performed in CU patients and, in six of them, skin biopsy specimens were taken from wheals to evaluate the immunohistochemical expression of VEGF and eosinophil cationic protein (ECP).
Results:  Plasma VEGF concentrations were higher in CU patients (8.00 ± 0.90 pmol/l) than in controls (0.54 ± 0.08 pmol/l) ( P  =   0.0001) and tended to parallel both the severity of CU and to correlate with F₁₊₂ levels. APST was positive in 85.1% of patients. VEGF concentration was significantly higher in APST-positive than in APST-negative patients ( P  =   0.0003). Immunohistochemically, all specimens from patients with CU showed a strong expression of VEGF ( P  =   0.002) that colocalized with ECP, a classic eosinophil marker.
Conclusions:  VEGF plasma levels are elevated in CU and parallel the disease severity. This supports a possible role of this molecule in CU pathophysiology. Eosinophils are the main cellular source of VEGF in CU lesional skin.     

Assessment of histamine-releasing activity of sera from patients with chronic urticaria showing positive autologous skin test on human basophils and mast cells

BACKGROUND: All previous studies agree that only a proportion of sera from patients with chronic urticaria (CU) positive on the autologous serum skin test (ASST) are able to induce histamine release in vitro. A non-specific release of bradykinins during clotting of blood samples has been suggested; however, ASST seems rather specific and some data point to the existence of a mast cell-specific histamine-releasing factor. OBJECTIVE: To assess whether, and to what extent, the use of both human basophils and mast cells increases the sensitivity of in vitro histamine release assays (HRAs) in ASST-positive patients with CU. METHODS: The histamine-releasing activity of sera from 93 patients with CU selected on the basis of strong skin reactivity on ASST was assessed in vitro on basophils from 1 (n=86), 2 (n=31), or 3 (n=20) normal donors, and on mast cells from 1 (n=3), 2 (n=3), or 3 (n=87) normal donors. RESULTS: Sera from 88/93 (95%) patients induced significant histamine release from mast cells or basophils on at least one HRA. 76/93 (82%), 45/90 (50%), 22/80 (28%), and 6/12 (50%) sera were able to induce significant histamine release from cells of 2/5, 3/5, 4/5 and 5/5 donors, respectively. CONCLUSION: Sera from nearly all ASST-positive patients with CU are able to induce histamine release in vitro. However, the serum from each single patient seems to show its maximal activity on autologous mast cells in vivo, and functional in vitro tests show much variability and seem less sensitive than ASST in the detection of patients with histamine-releasing factors in their blood.     

Validation of basophil histamine release against the autologous serum skin test and outcome of serum-induced basophil histamine release studies in a large population of chronic urticaria patients

BACKGROUND: Endogenous histamine-releasing factors (HRFs) are involved in 30-60% of patients with chronic urticaria (CU). Evidence for their existence comes from in vivo studies of autoreactivity with the autologous serum skin test (ASST), in vitro immunoassays demonstrating autoantibodies against the immunoglobulin E (IgE) or the high affinity IgE receptor (FcepsilonRI) and serum-induced histamine release (HR) from basophils and mast cells. We have examined the correlation between the ASST and a new basophil histamine-releasing assay (the HR-Urtikaria test) in a group of well-characterized CU patients and subsequently determined the frequency of HR-Urticaria-positive sera from a larger population of CU patients. SUBJECTS: Group 1 consisted of 28 patients with CU (16 were ASST-positive) 20 patients with atopic dermatitis, 24 patients with allergy to birch and nine healthy controls. Group 2 consisted of 873 unselected CU patients. METHODS: White blood cells containing 1-2% basophils from a healthy nonatopic donor were incubated with patients sera in the presence of interleukin (IL)-3. Histamine was measured by the glass fibre method. RESULTS: Using the ASST as the true outcome, the HR-Urticaria test showed a sensitivity and specificity of 75% in group 1 using a cut-off value for HR of >16.5%. None of the controls was positive in the HR-Urticaria test. In group 2, we found no difference in the frequency of positives between male (34.6%, n = 254) and female adults (35.1%, n = 576) but twice as many females as males were tested. CONCLUSIONS: Our studies have shown that the HR-Urticaria test has a good sensitivity and specificity for endogenous HRFs demonstrated by the ASST in patients with CU and that about one-third of unselected patients with CU have a positive result.     

Activation of the tissue factor pathway of blood coagulation in patients with chronic urticaria

BACKGROUND: In patients with chronic urticaria (CU), plasma shows signs of thrombin generation and autologous plasma skin tests score positive in as many as 95% of cases. OBJECTIVE: To evaluate the initiators of blood coagulation that lead to thrombin generation and fibrinolysis in CU. METHODS: Activated factor VII, activated factor XII, fragment F(1+2), and D-dimer plasma levels were measured in 37 patients with CU and 37 controls. Skin specimens from 10 patients with CU and 10 controls were tested for tissue factor immunohistochemically. RESULTS: Mean F(1+2) levels were higher in patients than controls (2.54 [SD 2.57] nmol/L vs 0.87 [0.26] nmol/L; P < .001); disease activity was moderate or severe in 9 of 11 (82%) and 9 of 26 (35%) patients showing high or normal F(1+2) levels, respectively (P < .025). Mean D-dimer plasma levels were higher in patients than controls (329 [188] ng/mL vs 236 [81] ng/mL; P < .01); disease activity was moderate or severe in 6 of 8 (75%) and 11 of 29 (38%) showing elevated or normal plasma D-dimer levels (P = NS). Factor VIIa levels were higher in patients than controls (2.86 ng/mL [0.66] vs 1.97 ng/mL [0.65]; P < .001). Activated factor VII and F(1+2) levels were correlated (r = 0.529; P = .008). Tissue factor reactivity was observed only in CU skin specimens. CONCLUSION: The extrinsic pathway of clotting cascade is activated in CU. Disease severity is associated with the activation of the coagulation cascade. CLINICAL IMPLICATIONS: The involvement of the coagulation pathway in CU opens new perspectives for a better understanding of the pathogenesis and, possibly, for the treatment of this disease.     

Serum-induced basophil CD63 expression by means of a tricolour flow cytometric method for the in vitro diagnosis of chronic urticaria

BACKGROUND: Functional autoantibodies against the alpha-chain of the high-affinity IgE receptor (FcepsilonRIalpha) identify a subset of patients with chronic urticaria (CU) due to autoreactivity, as assessed by an in vivo positive response to autologous serum skin test (ASST). We performed a study to standardize the serum-induced basophil activation assay by flow cytometry (FCM) using a new tricolour method, assessing the diagnostic performance of this test in discriminating between ASST+ and ASST- CU patients. METHODS: Sera of 64 CU patients (22 ASST+ CU and 42 ASST- CU) and 10 healthy subjects were tested for their ability to induce basophil CD63 expression when incubated with whole blood of both atopic (DA) and non-atopic donors (DNA). Using a triple-labelled strategy with anti-CD123, anti-HLA-DR and anti-CD63 antibodies, CD63+ basophils were identified on a selected population of CD123+ HLA-DR- cells. In 3 ASST+ CU patients who underwent cyclosporine therapy, the assay was performed before and after treatment. RESULTS: The ASST+ CU sera resulted in a significant higher induction of basophil CD63 expression compared with ASST- CU and healthy donors sera; when whole blood from DA was used, sensitivity and specificity of the assay were 95.5% and 90.5% respectively. ASST+ CU serum activity was significantly decreased during cyclosporine A treatment, in parallel with clinical remission. CONCLUSIONS: Chronic urticaria serum-induced CD63 expression assay performed on DA whole blood by means of our tricolour FCM method could be the most useful tool for identification of a subset of patients with autoimmune CU and may become a promising tool also for monitoring treatment efficacy.     

Circulating level of the platelet-derived CXC chemokine platelet factor 4 in chronic urticaria patients with or without coexistent euthyroid Hashimoto's thyroiditis

The concept of autoimmune aetiology of some cases of chronic urticaria (CU) has been supported by several observation including wheal-and-flare reaction induced by intradermal injection of autologous serum as well as association with other autoimmune diseases, in particular Hashimoto's thyroiditis (HT). It is known that activated platelets may actively participate in immune-inflammatory processes. Therefore, we assessed whether autoimmune phenomenon associated with CU influence the systemic platelet activity measured by circulating level of platelet factor 4 (PF-4). Plasma level of PF-4 was analysed using enzyme-linked immunosorbent assay in twelve women with strong positive response to autologous serum skin test (ASST) suffering from CU, twelve female patients with strong positive ASST suffering from both CU and untreated, HT as well as sixteen healthy women. All the subjects were clinically and biochemically euthyroid. There were no statistically significant differences between the CU patients with or without euthyroid HT and plasma PF-4 level in healthy controls. In patients with both CU and thyroiditis, plasma level of PF-4 did not correlate significantly with the level of antibodies against thyroperoxidase. It seems that circulating level of the platelet-derived chemokine is not increased in CU patients with positive response to ASST, regardless the occurrence of euthyroid HT.     

Helicobacter pylori infection: prevalence in chronic urticaria patients and incidence of autoimmune urticaria (study in Dr. Cipto Mangunkusumo Hospital, Jakarta)

AIM: To determine the prevalence of Hp infection in patients with chronic urticaria (CU) and to evaluate the result of autologous serum skin test (ASST) in CU patients with Hp infections. METHODS: In this cross-sectional study, 16 patients with chronic urticaria and 16 non-urticaria volunteers were investigated (matched for age and sex). All subjects were examined for Hp infection with the 13C-urea breath test. Autologous serum skin test was performed in patients with proven Hp infection. RESULTS: Helicobacter pylori was detected in 12.5% of patients and 0% of the control group. There was no significant difference between the two groups (p = 0.484 using Fisher exact test). Autologous serum skin test was positive in 1 of 2 CU patients with Hp infection. CONCLUSION: In this study, there was no significant difference in the seroprevalence of Hp infection between CU patients and controls. Autologous serum skin test was positive in 1 of 2 CU patients with Hp infection.     

Assessment of circulating FCεRIa in Chronic Spontaneous Urticaria patients and its correlation with clinical and immunological variables

Chronic spontaneous urticaria (CSU) is a chronic type characterized by episodes of wheals with or without angioedema. Autoantibody against the alpha subunit of Fc epsilon receptor (FcεRIa) was detected in CSU patients' sera. The study aims to evaluate the clinical utility of skin tests in CSU patients. In addition, it assesses the presence of circulating FcεRIa in CSU patients and their correlation with other clinical and immunological variables. The study includes 40 healthy controls and 40 CSU patients who had urticaria symptoms for at least 8 weeks. All subjects underwent the following tests: autologous serum skin test (ASST), autologous plasma skin test (APST), immunoglobulin E (IgE), antinuclear antibodies (ANA), antithyroid antibodies (ATA). An in-house enzyme-linked immunosorbent assay was used for FcεRIa detection. The prevalence of ANA and ATA in CSU was 7.5% and 20% respectively. Total IgE was significantly higher in CSU than in controls (p?<?0.0001). The study detected circulating antibody to FcεRIα in 2.5% of controls and 52.5% of CSU patients (p?<?0.0001). The prevalence of antibody to FcεRIa was 27.3% and 83.3% of ASST negative and positive patients respectively (p?=?0.0004). But the prevalence was 17.6% and 78.3% of APST negative and positive patients respectively (p?=?0.0002). In conclusion, Circulating antibody to FcεRIa has a role in the pathogenic mechanisms of CSU.     

High prevalence of autoimmune urticaria in children with chronic urticaria

BACKGROUND: The etiology of chronic urticaria (CU) in childhood often remains unrecognized. Recently, in adults it has been shown that approximately 40% of patients with CU have autoimmune urticaria (AU); however, no data are available in children. OBJECTIVE: To determine the prevalence and possible risk factors for AU in children with CU. METHODS: Ninety-three consecutive children (52 male; median age, 7.8 years) with CU were evaluated for AU by means of autologous serum skin test (ASST) in all and serum-induced basophil histamine release (HR-urticaria test) in 52. All other known causes of CU were excluded as appropriate. RESULTS: A cause for CU was identified in 44 children (47%), whereas 49 (53%) remained idiopathic. ASST and HR-urticaria test had positive results in 22 of 49 (45%) and in 16 of 31 (52%) children with idiopathic CU compared with 1 of 44 (2%) and 5 of 21 (24%) with CU of a known cause, respectively ( P <.00001; P=.09). Sensitivity, specificity, and positive and negative predictive values of the ASST for diagnosing AU are 78%, 85%, 74%, and 88%. The prevalence of AU in childhood is 31% (15/52; 95% CI, 24%-51%). None of the variables studied were predictive for development of AU. CONCLUSION: Our results demonstrate for the first time that children have the same ability as adults to produce functionally active autoantibodies directed against IgE or IgE receptor and that AU occurs in children in as many as 30% of cases. The addition of screening for AU dramatically decreases the rate of the idiopathic form from 52% to 20%.     

Detection of circulating IgG autoantibody to FcεRIα in sera from chronic spontaneous urticaria patients

BackgroundsChronic spontaneous urticaria (CSU) is a common skin disorder characterized by itchy wheals of at least 6 weeks in duration, wherein the autoimmune mechanism is involved to activate IgE receptors (FcεRIα) on mast cells. We aimed to assess levels of IgG autoantibody against FcεRIα in sera from CSU patients using dot-blot immunoassay.MethodsWe performed a hospital-based cross-sectional study of 125 CSU patients (64 ASST-positive, 61 ASST-negative) and 64 age-and sex-matched healthy controls. The cut-off value of IgG FcεRIα autoantibody was determined as the mean intensity plus two standard deviations of values in controls. Positivity for IgG autoantibody to FcεRIα was analyzed according to clinical parameters of disease duration, urticaria activity score (UAS), ASST, response to antihistamine treatment, complement levels, and the presence of other autoantibodies. Nonparametric tests were applied for statistical analyses.ResultsIgG positivity to FcεRIα was noted in 24.8% of CSU patients and was significantly more frequent in ASST-positive patients than in ASST-negative patients (32.8% vs 16.4%, P = 0.040). Only 3.1% of healthy controls had this autoantibody. Complement 3 levels were significantly lower in anti-FcεRIα antibody-positive patients than antibody-negative patients (109.8 ± 19.9 vs 123.1 ± 30.9, P = 0.035). No significant associations were found between IgG positivity to FcεRIα and UAS, serum total IgE levels, atopic status, clinical responses to antihistamines, or the presence of anti-thyroid and anti-nuclear antibodies.ConclusionThese findings suggest that circulating IgG autoantibody to FcεRIα in a subset of patients may be involved in the autoimmune mechanism of CSU. Further studies are needed to clarify its clinical significance.     

The autologous serum skin test in the follow-up of patients with chronic urticaria

BACKGROUND: The presence of anti-FcepsilonRI and anti-IgE autoantibodies in a subset of patients with chronic urticaria suggests their aetiopathogenetic role. In clinical practice, the presence of these antibodies is usually considered when the autologous serum skin test (ASST) is positive. AIMS: To evaluate if the positive ASST follows up the activity of chronic urticaria. METHODS: Autologous serum skin test and thyroid autoantibody detection were performed in 82 patients with chronic urticaria and repeated 1 year later, when the vast majority of patients were symptom-free. Twenty patients with Hashimoto thyroiditis (HT), who had never suffered from urticaria, represented the control group. RESULTS: At the start of the study, the prevalence of positive ASST was 46.6%. The association of HT-urticaria was 29.3%. ASST was positive in 62 and 39% of patients with and without HT, respectively (P > 0.05 ns). One year later, 28 of 34 patients with a positive ASST were symptom-free, but 50% of them were positive for ASST. The ASST was positive in 86.7 and 8% of patients with and without HT, respectively (P < 0.001). In the control group, ASST was always negative. CONCLUSIONS: The co-existence of autoimmune thyroiditis with chronic urticaria seems to induce a significant difference in the persistence of a positive ASST. Consistent with previous reports, a positive ASST correlates with disease exacerbation in chronic urticaria patients without thyroiditis. In patients with thyroiditis and urticaria, positive ASST persists even after the urticaria has disappeared, thus questioning whether a positive ASST to be a surrogate marker of the functional role of anti-FcepsilonRI and anti-IgE autoantibodies.     

EAACI/GA2LEN task force consensus report: the autologous serum skin test in urticaria

Injection of autologous serum collected during disease activity from some patients with chronic spontaneous urticaria (CU) into clinically normal skin elicits an immediate weal and flare response. This observation provides a convincing demonstration of a circulating factor or factors that may be relevant to the understanding of the pathogenesis and management of the disease. This test has become known as the autologous serum skin test (ASST) and is now widely practised despite incomplete agreement about its value and meaning, the methodology and the definition of a positive response. It should be regarded as a test for autoreactivity rather than a specific test for autoimmune urticaria. It has only moderate specificity as a marker for functional autoantibodies against IgE or the high affinity IgE receptor (FcεRI), detected by the basophil histamine release assay, but high negative predictive value for CU patients without them. It is usually negative in other patterns of CU, including those that are physically induced. Positive ASSTs have been reported in some subjects without CU, including those with multiple drug intolerance, patients with respiratory allergy and healthy controls, although the clinical implications of this are uncertain. It is essential that failsafe precautions are taken to ensure that the patient's own serum is used for skin testing and aseptic procedures are followed for sample preparation and handling. CU patients with a positive ASST (ASST⁺) are more likely to be associated with HLADR4, to have autoimmune thyroid disease, a more prolonged disease course and may be less responsive to H1-antihistamine treatment than those with a negative ASST (ASST⁻) although more evidence is needed to confirm these observations conclusively.     

Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria

BACKGROUND: Recent studies have found that most otherwise normal subjects with a history of acute urticaria induced by several nonsteroidal anti-inflammatory drugs (NSAIDs) show a wheal-and-flare reaction on intradermal injection of autologous serum. This phenomenon has been previously observed in patients with chronic urticaria (CU) and suggests a possible common background in CU and NSAID-induced urticaria. A relationship between these 2 conditions is further suggested by the fact that up to 30% of patients with CU have a worsening of their skin disorders after the ingestion of chemically unrelated NSAIDs. OBJECTIVE: I sought to assess whether otherwise normal subjects with multiple or single NSAID intolerance show a propensity to have CU. METHODS: Two hundred eighty otherwise normal patients with an unequivocal history of acute urticaria induced by NSAIDs seen during the last 10 years were studied. On the basis of both clinical history and oral challenge tests with at least 2 alternative NSAIDs, the patients were classified as having single or multiple NSAID intolerance. All the patients were re-evaluated within the end of 2002, 1 to 10 years after the first visit, to assess the onset of CU. One hundred allergic adults without a history of CU and of drug allergy followed up for 1 to 10 years were used as control subjects. RESULTS: One hundred fifty-nine and 121 patients were finally considered as having single or multiple NSAID intolerance, respectively. At the follow-up visit, 93 (33%) of 280 patients had CU. The prevalence of CU was very similar in subjects with single or multiple NSAID intolerance (48/159 [30%] vs 45/121 [37%], respectively; P = not significant). Only 1 (1%) of 100 atopic control subjects had CU during the follow-up period (P <.001). Among single NSAID reactors, patients who had CU had a significantly higher prevalence of intolerance to aspirin than those who did not have CU (36/48 [75%] vs 41/111 [37%], P <.001), whereas the latter had a markedly higher prevalence of intolerance to pyrazolone drugs (52/111 [47%] vs 10/48 [21%], P <.01). Altogether, only 12 (15%) of 82 patients intolerant to drugs other than aspirin versus 36 (47%) of 77 aspirin reactors had CU (P <.001). CONCLUSION: NSAID intolerance might precede the onset of CU by years. Both multiple and single NSAID reactors with a history of aspirin-induced urticaria seem at higher risk for CU than patients with a history of single intolerance to NSAIDs other than aspirin.     

Autologous serum skin test in chronic idiopathic urticaria: prevalence, correlation and clinical implications

Some cases of chronic idiopathic urticaria (CIU) have histamine-releasing IgG autoantibodies in their blood. This disease subgroup is called "autoimmune urticaria". To date, the autologous serum skin test (ASST) is the best in vivo clinical test for the detection of basophil histamine-releasing activity in vitro. This study aimed to find the prevalence of ASST positive cases in Thai patients with CIU, to identify factors related to the positivity of ASST and to find the clinical implications of ASST in CIU. A retrospective study was performed among 85 CIU patients who attended the Urticaria Clinic at the Department of Dermatology, Siriraj Hospital and were willing to perform ASST, from January 2002 to December 2003. Twenty-one (24.7%) patients had a positive ASST. There was no significant difference between patients with positive ASST and negative ASST as to the severity of the disease (wheal numbers, wheal size, itching scores and the extent of body involvement) as well as the duration of the disease.     

The addition of zafirlukast to cetirizine improves the treatment of chronic urticaria in patients with positive autologous serum skin test results

BACKGROUND: Because leukotrienes have potent local effects on cutaneous vasculature, leukotriene antagonists might be effective in the treatment of chronic urticaria. OBJECTIVE: A double-blinded, placebo-controlled trial comparing cetirizine 10 mg daily in combination with zafirlukast 20 mg twice a day versus cetirizine 10 mg daily and placebo was conducted to determine whether subjects with chronic urticaria benefit from add-on therapy with a leukotriene-modifying agent. METHODS: Patients 12 years or older with a history of chronic urticaria (more than 6 weeks in duration) required diary documentation of 6 or more hives on at least 2 days/week and a suboptimal response to H(1)-antagonist therapy for enrollment. At baseline, all subjects were skin tested to autologous serum to assess for the potential presence of FcepsilonRI or IgE autoantibodies. Subjects meeting the initial entry criteria were treated with cetirizine 10 mg a day and placebo twice daily for 1 week. Those patients with persistent hives were randomized to receive cetirizine 10 mg daily and zafirlukast 20 mg twice a day or cetirizine 10 mg daily and placebo. At each successive weekly visit, physician and patient treatment effectiveness score (TES) and visual analog scale (VAS) ratings were recorded. Statistical analysis used generalizing estimating equations to compare the effect of combination therapy versus monotherapy on TES and VAS ratings. Results were adjusted for baseline rating, recruiting center, and autologous serum skin test (ASST). A separate analysis evaluated patients with positive ASST results receiving combination therapy versus monotherapy. RESULTS: Combination therapy with zafirlukast demonstrated a modest but significantly greater improvement compared with cetirizine monotherapy in physician and patient recorded VAS ratings at visit 4 and across treatment visits 4 through 6 (P <.05 unless stated otherwise). Subjects with ASST positive results receiving combination therapy as compared with subjects with negative ASST results exhibited a significant improvement in patient recorded VAS ratings across visits 4 through 6. Subgroup analysis of subjects with ASST positive results receiving combination therapy versus monotherapy showed improvement in physician recorded TES at visit 5, physician recorded VAS at visits 4 and 5 and across visits 4 through 6, as well as for patient recorded VAS at visit 5. There were no significant results for patients with ASST negative results. CONCLUSION: The results of this study indicate that only patients with autoimmune (ASST positive) chronic urticaria refractory to H(1)-antagonist monotherapy might benefit from the addition of the leukotriene D(4)-receptor antagonist zafirlukast to their treatment regimen. These results also suggest that routine screening of patients with chronic urticaria with the ASST might be useful in formulating therapeutic algorithms in the management of chronic urticaria.     

Prognostic Factors for Chronic Spontaneous Urticaria: A 6-Month Prospective Observational Study

Purpose

Chronic urticaria (CU) has a substantial impact on the quality of life. Little clinical data on the prognosis of CU has been reported. This study aimed to investigate the control status and remission rate of CU and to explore potential predictors of good responses to the treatment during a 6-month treatment period.

Methods

A total of 75 patients with chronic spontaneous urticaria (CSU) were enrolled from 3 university hospitals in Korea. Urticaria control state was classified into 2 groups: group I (remission and well-controlled) and group II (partly and uncontrolled). CU-specific quality of life (CU-QoL) and the urticaria activity score (UAS) were measured before and after the treatment. Autologous serum skin test (ASST), and anti-nuclear and anti-thyroid antibodies were measured at the enrollment into the study. Aspirin intolerance was confirmed by an oral provocation test.

Results

Of 59 patients completing the study, 21 (35.6%) arrived at well-controlled status and only 2 (3.4%) achieved remission, whereas 26 (44.1%) remained at partly controlled status and 10 (16.9%) were at uncontrolled status. Mean changes in CU-QoL (36.5±2.7 vs 20.6±4.3, P=0.017) and UAS (-7.9±0.8 vs -3.0±1.0, P=0.001) were significantly different between groups I and II. The presence of serum autoantibodies and aspirin intolerance had no influence on the control of urticaria in this study. However, ASST positivity was identified as a significant predictor of CU control in multivariate analysis (OR=6.106, P=0.017).

Conclusions

The proportion of CSU patients that achieved remission or a well-controlled state was 39% for the 6 months of stepwise treatment. Longer observations are necessary to assess the exact prognosis of CSU. ASST results may be a useful parameter for predicting a better response to treatment and both UAS and CU-QoL are helpful to monitor therapeutic response.     

Autologous serum skin test reactivity in patients with non-allergic asthma

BACKGROUND: Inflammatory alterations of respiratory airways have been found in patients with non-allergic asthma, but the triggering event has not been defined. An autoimmune activation of inflammatory cells has been hypothesized. OBJECTIVE: To evaluate whether histamine-releasing factors are present in sera from non-allergic asthmatics. METHODS: Twenty-four patients with non-allergic asthma underwent in vivo autologous serum skin test (ASST) and in vitro basophil histamine release assay using autologous basophils as well as basophils from normal donors. Twenty-seven subjects with respiratory allergy and three normal subjects were chosen as control. RESULTS: ASST was positive in 14/24 non-allergic asthmatics (58%) whereas it was negative in all 30 control subjects (P<0.001). The serum of only one ASST-positive patient out of 12 (8.4%) induced in vitro histamine release from autologous basophils. The serum from another ASST-positive patient induced histamine release from membrane IgE-stripped autologous basophils. Sera from either non-allergic asthmatics or from control subjects did not provoke significant histamine release from basophils from three normal donors. CONCLUSION: Skin reactivity to autologous serum is common among non-allergic asthmatics, indicating the presence of circulating histamine-releasing factors. However, only in a minority of patients in vitro functional evidence of histamine-releasing autoantibodies (anti-FcepsilonRI or anti-IgE) was obtained. The presence of circulating histamine-releasing factors might contribute to initiation/maintenance of inflammation in respiratory airways of non-allergic asthmatics.     

Matrix metalloproteinase‐9: a novel biomarker for monitoring disease activity in patients with chronic urticaria patients?

Background:  Matrix metalloproteinase (MMP)-9, an enzyme that contributes to inflammatory responses and subsequent tissue remodelling, has recently been suggested to be a good biomarker for monitoring disease activity in patients with chronic urticaria (CU). Here, we assessed whether total MMP-9 and/or active MMP-9 plasma levels are increased and correlated to disease activity in patients with CU.
Methods:  Total MMP-9 and active MMP-9 plasma levels were determined by ELISA in 70 CU patients and control subjects (patients with psoriasis and healthy controls). CU activity was measured using weekly and daily composite symptom scores (urticaria activity score) calculated from the number of wheals and the intensity of pruritus.
Results:  Significantly increased levels of total and active MMP-9 were detected in patients with CU as compared to healthy controls. Interestingly, patients with psoriasis also had clearly elevated plasma levels of total and active MMP-9, indicating that MMP-9 plasma levels do not specifically reflect CU activity. Most notably, total and active MMP-9 levels were not correlated with disease activity in CU or psoriasis patients.
Conclusion:  Plasma MMP-9 is not a good CU biomarker and should not be used for assessing the efficacy of treatment in CU patients or their spontaneous changes in disease activity.