A 4-year follow-up study of atopic dermatitis therapy with 0.1% tacrolimus ointment in children and adult patients.

BACKGROUND: For the treatment of a chronic disease like atopic dermatitis, sustained tolerability and efficacy of the applied medication are essential. OBJECTIVES: The present open-label, noncomparative study was conducted to obtain information on the long-term safety and efficacy of 0.1% tacrolimus ointment. METHODS: Patients aged 2 years or older with an affected body surface area of more than 5%, who previously participated in a clinical trial on tacrolimus ointment, were eligible for this study. The treatment area was defined by the investigator at study entry. Both children and adults applied continuously or intermittently 0.1% tacrolimus ointment twice daily during episodes of active disease plus an additional week after remission over a follow-up period of up to 4 years. RESULTS: The intent-to-treat population comprised 782 patients, with a median age of 22 years (range 2-72). Patients remained in the study for up to 4 years. Approximately half of the patients discontinued the study prematurely; the median follow-up was 1422 days. Median tacrolimus ointment use was 31.2 g during the first week; ointment use decreased during the first year and then remained stable for the remainder of the study. The median cumulative tacrolimus use was 271.5 g at month 6, 462.5 g at month 12, 739.9 g at month 24, 1029.3 g at month 36 and 1320.8 g at month 48. Altogether 51.8% of patients discontinued the study prematurely; the main reasons were withdrawal of consent (13.3%), loss to follow-up (11.3%) and lack of efficacy (9.4%). Adverse events led to study discontinuation in 3.7% of the patients. The most frequent application site events were skin burning and pruritus. These events were most often reported in adult patients during the initial treatment period; prevalence decreased after the first week and remained at a low level throughout the study. Nonapplication site events occurred with stable incidences throughout the study period. In general, calculated daily hazard rates did not indicate an increased risk of adverse events with prolonged treatment. The total affected body surface area decreased substantially upon onset of treatment and efficacy of treatment was maintained until the end of the study with smaller but continuous improvements throughout the follow-up period. Overall, 75% of the patients and 76% of the investigators rated their satisfaction with the treatment as excellent, very good or good at the end of the study or at the time of premature discontinuation. CONCLUSIONS: The safety profile of intermittent or continuous long-term application of 0.1% tacrolimus ointment for up to 4 years was consistent with that which has been established from shorter studies and gave no reason for concern. In addition, 0.1% tacrolimus ointment demonstrated sustained efficacy as reflected by the expression of high satisfaction with treatment by both patients and investigators.

Patch test reactions to cosmetic allergens in 1995-1997 and 2000-2002 in Finland--a multicentre study.

Contact sensitivity to cosmetics is common, but the sensitizing chemicals vary between countries and study periods. The present survey aimed at revealing the recent trends in patch test sensitivity with cosmetic chemicals in Finland. We report a retrospective multicentre survey of patch test reactions focusing on cosmetic-related substances and comparing the test results in 1995-97 with those in 2000-02. The most striking increases in the frequency of the patch test sensitivity were found with balsam of Peru and propolis from 4.0% to 6.2% (P < 0.001) and from 0.5% to 1.4% (P < 0.001), respectively, whereas the most prominent decreases were found with methylchloro/methylisothiazolinone and chlorhexidine diglugonate from 2.4% to 1.3% (P < 0.001) and from 1.2% to 0.5% (P < 0.001), respectively. The level of patch test sensitivity to methyldibromo glutaronitrile increased, although not significantly, from 1.0% to 1.5%. An increasing tendency was also found with hair dye chemicals 4-aminophenol and toluene-2,5-diamine or toluene-2,5-diamine sulfate from 1.3% to 3.8% and from 1.4% to 5.2%, respectively, while such a tendency was not found among permanent wave chemicals. The sensitivity level of fragrance mix remained the same (6% - 7%). We conclude that surveys revealing the state of sensitivity to cosmetic chemicals should be performed periodically in different countries.

Immediate hypersensitivity to Malassezia furfur and Candida albicans mannans in vivo and in vitro.

BACKGROUND: Elevated and correlative Malassezia furfur (M. furfur) and Candida albicans (C. albicans) mannan-specific IgE have been demonstrated in atopic eczema dermatitis syndrome (AEDS) of the head, neck and shoulder (HNS) region of the skin. The significance of these antibodies in vivo has not been demonstrated. METHODS: Sixty-five AEDS patients with HNS distribution were included. Serum total IgE (S-IgE) and yeast antigen-specific (Cetavlon-purified mannan and whole extract antigens of M. furfur and C. albicans) IgE were measured and skin prick tests (SPT) were performed with the yeast antigens. RESULTS: Mannan-specific IgE and SPT were positive in 51 and 48% of patients with M. furfur and in 42 and 22% with C. albicans, respectively. Whole extract-specific IgE and SPT were positive in 85 and 95% of patients with M. furfur and in 91 and 57% with C. albicans, respectively. The highest correlation between specific IgE and SPT was seen with M. furfur mannan (r = 0.60; P < 0.0001). Both M. furfur mannan-specific IgE (r = 0.76; P < 0.0001) and SPT (r = 0.44; P = 0.0005) correlated with S-IgE. CONCLUSIONS: Mannan-induced immediate hypersensitivity in vivo was demonstrated in SPT. The significant correlation between M. furfur mannan-specific IgE and SPT suggests that mannan is an important allergen in yeast hypersensitive AEDS in vivo.

Nickel allergy and orthodontic treatment.

OBJECTIVES: Tolerance induction to prevent development of nickel allergy has been suggested with permanent dental braces. We wanted to find out which effect orthodontic treatments had had on the development of nickel allergy in university students. STUDY DESIGN: We examined and patch tested 153 students, of whom 113 had a history of pierced skin, and 70 a history of orthodontic treatment roughly 10 years earlier. RESULTS: All except one student with pierced skin were females. Development of nickel allergy was significantly associated with skin piercing (54% compared with 12%). At the time of the study, there was a slight but non-significant difference in the prevalence of nickel allergy between students who had been subjects for orthodontic treatment (49%) compared with non-treated ones (58%) if they had pierced skin. There were no significant differences in the development of nickel allergy among students who had had permanent dental braces before (50%) or after skin piercing (48%). However, from 40 students without skin piercing four of 11 (three males) with a history of permanent braces had developed nickel allergy, as compared with none of 22 (P = 0.008) without orthodontic treatment suggesting possibility of sensitization through dental devices. CONCLUSIONS: Orthodontic treatment may not lead to tolerance induction on all occasions, and sensitization through permanent devices seems to be possible.

IgE-binding components of cultured human keratinocytes in atopic eczema/dermatitis syndrome and their crossreactivity with Malassezia furfur.

BACKGROUND: Atopic eczema/dermatitis syndrome (AEDS) patients display immunoglobulin E (IgE) reactivity to several antigens, e.g. saprophytic yeasts as Malassezia furfur. AEDS patients also show IgE autoreactivity towards cells of their own tissue including epidermis. PURPOSE OF THE STUDY: The aim of this study was to investigate the IgE autoreactivity of AEDS patients to cultured keratinocytes and to reveal potential crossreacting epitopes in cultured keratinocytes and M. furfur. MATERIAL AND METHODS: Serum samples of 27 AEDS patients were analyzed, of these 13 were M. furfur radioallergosorbent test (RAST) positive and 14 negative. Four urticaria, three psoriasis, and seven nonatopic patients were included as controls. The studies were performed by using IgE immunoblotting and immunoblotting inhibition methods. RESULTS: Ten IgE-binding protein bands were detected in cultured human keratinocytes by IgE immunoblotting using sera from adult AEDS patients. Anti-keratinocyte IgE antibodies were more associated with elevated S-IgE level than M. furfur RAST. Clear crossreactivity with M. furfur could not be shown. CONCLUSIONS: The possible pathomechanism of anti-keratinocyte IgE antibodies is not due to IgE epitope mimicry of saprophytic yeast and local tissue in AEDS skin.

Mast cells and IgE-containing cells in gastric mucosa of Helicobacter pylori infected and non-infected patients with chronic urticaria.

BACKGROUND: Several studies have indicated that antibiotic therapy aimed at eradication of Helicobacter pylori has effects on symptoms of chronic urticaria (CU) patients. However, the possible connections and pathomechanism by which H. pylori might be linked to CU have remained largely unknown. The IgE-mediated pathway might be a possible link between H. pylori infection and CU. We therefore clarified the role of H. pylori as an inducer of IgE response. MATERIALS AND METHODS: Gastroscopy was performed and mucosal biopsy specimens were taken to evaluate the histology, as well as the presence of H. pylori bacteria, mast cells and IgE-containing cells in the antral mucosa, in 21 CU patients. Controls (n = 48) included 19 patients with lichen planus, nine patients with atopic dermatitis and 20 patients with no skin or allergic disease. RESULTS: The mean densities of IgE-containing cells were significantly higher in H. pylori-infected patients and in patients with skin disease compared to non-H. pylori-infected patients with no skin or allergic disease. No significant difference was found in the number of IgE-containing cells between H. pylori-infected and non-infected patients with CU. There was no significant difference in the mean densities of mast cells in the different patient groups. CONCLUSIONS: Our findings suggest that H. pylori gastritis leads to increased IgE production. However, we could not show a significant difference in IgE staining between H. pylori-infected and non-infected patients with CU.

Food hypersensitivity among Finnish university students: association with atopic diseases.

BACKGROUND: Food hypersensitivity (FH) is commonly suspected, especially among adults with atopic diseases. Symptoms of FH vary from oral allergy syndrome (OAS) to gastrointestinal, respiratory and systemic reactions. More data are needed regarding patient groups at risk for FH, and symptoms and foods responsible for the reactions. METHODS: FH was studied in 286 Finnish university students. Four study groups were selected: subjects (i) with current atopic dermatitis (AD) with or without allergic rhinoconjunctivits (ARC) or asthma (n = 41); (ii) with past AD with or without ARC or asthma (n = 89); (iii) with ARC or asthma (n = 69); (iv) without clinically confirmed atopic disease (n = 87). A thorough clinical examination was performed with a questionnaire specifying adverse events to foods. In addition, IgE specific to five foods, and skin prick tests to four foods were determined. RESULTS: FH was reported by 172 subjects (60.1%), more often by females (66.3%) than by males (47.9%) (P = 0.003). FH was most frequent among subjects with AD, among those with current AD in 73.2%, with past AD in 66.3%, and with ARC or asthma in 63.8%; 44.8% of subjects without any atopic disease reported FH. Kiwi fruit caused symptoms most frequently (38.4%), followed by milk (32.6%), apple (29.1%), tomato (27.9%), citrus fruits (25.0%), tree nuts (23.3%), and peanut (17.4%). A total of 720 separate symptoms to 25 food items were reported. OAS was most common (51.2%), followed by gastrointestinal symptoms (23.5%), worsening of AD (11.4%), urticaria (4.2%), rhinitis or conjunctivitis (5.7%) and asthma (4.0%). Severe reactions occurred in 3.5% (25/720). Negative IgE and skin prick test to foods predicted well negative history, but the value of positive test results was limited. CONCLUSIONS: FH was reported most often by students with current AD and multiple atopic diseases. Severe reactions occurred especially in patients with ARC and asthma. After excluding lactose intolerance, milk hypersensitivity was frequently reported.

Cutaneous adverse reactions to clindamycin: results of skin tests and oral exposure.

BACKGROUND: Clindamycin is an antibiotic used in anaerobic and severe complicated infections. It is often selected for patients with a history of allergy to other antibiotics. OBJECTIVES: To study the occurrence of clindamycin hypersensitivity and to determine whether skin tests are useful in cases of suspected clindamycin allergy. METHODS: Six patients with an exanthematous rash and a history strongly suggestive of clindamycin hypersensitivity were studied with skin tests and oral exposure. Cases of suspected adverse drug reactions to clindamycin reported to the National Register of Adverse Effects of Drugs (NRAED) in Finland during 1973-2000 were analysed. RESULTS: In the skin tests true-positive patch test reactions were seen in four of six patients, while 22 healthy control patients were negative. One false-positive and one false-negative patch test reaction were seen. During 1973-2000, 29 suspected cases of skin and/or mucosal membranes affected by clindamycin were reported to the NRAED. CONCLUSIONS: Clindamycin hypersensitivity is not common. Delayed-type allergic reactions occur and patch tests are useful in those cases. Oral exposure is the method of choice if possible, as false-negative and false-positive reactions may occur.

Extraction of IgE-binding components of Helicobacter pylori by immunoblotting analysis in chronic urticaria patients.

BACKGROUND: An association between Helicobacter pylori and chronic urticaria has been suspected previously. An IgE-mediated pathway might be a possible link between H. pylori infection and chronic urticaria, and therefore we wanted to prepare an optimal H. pylori antigen to detect H. pylori-specific IgE antibodies in chronic urticaria patients. METHODS: H. pylori antigen extracts were prepared in different ways to find the optimal antigen extract to be used in the assays. Immunoblotting was used to detect IgE-binding bands. The results were applied in an H. pylori RAST assay for specific H. pylori IgE antibodies in patient sera. RESULTS: In immunoblotting, the largest number of IgE-stained bands were visualized in the washing fluids and sonicated extracts, while strong heating and denaturing treatments destroyed the epitopes for IgE binding, suggesting that they belonged to the flagellar structures of H. pylori. However, in H. pylori-specific RAST analysis, specific IgE was found only in 1 of 25 H. pylori-infected patients. CONCLUSIONS: Our findings suggest that although IgE-binding epitopes were found in H. pylori, H. pylori-specific IgE antibodies are not common in chronic urticaria, and the clinical significance of the IgE response is unclear.

Systemic ketoconazole is an effective treatment of atopic dermatitis with IgE-mediated hypersensitivity to yeasts.

BACKGROUND: IgE-mediated hypersensitivity to yeasts is often seen in atopic dermatitis (AD) patients, especially when dermatitis is located in the head, neck, and shoulder regions. Two studies have shown the efficacy of ketoconazole in the treatment of this type of AD, in contrast to results of topical treatment. The objective was to assess the clinical efficacy of antifungal treatment in AD in a randomized, double-blind, placebo-controlled study with oral ketoconazole and yeast-specific IgE levels and saprophytic yeast growth monitored simultaneously. METHODS: Eighty patients with AD and positive P. ovale and/or C. albicans RAST/skin prick test results were randomized to receive ketoconazole or placebo for 30 days. The yeast growth of skin and pharynx; P. ovale, C. albicans, andS. cerevisiae RAST; serum total IgE; and the severity of the eczema (SCORAD) were assessed at day 0 and thereafter at 1 and 3 months. RESULTS: A significant improvement was seen in the SCORAD scale in the ketoconazole group at the second visit in comparison to the first visit (P<0.0005; n=36), but not in the placebo group (n=39). Of the individual determinants of the SCORAD, itching (P<0.005), the extent of dermatitis (area percentage), excoriation, lichenification (P<0.01), erythema, papulation, and dryness (P<0.05) improved significantly in the ketoconazole group. In the placebo group, only the extent of dermatitis (area percentage) decreased significantly (P<0.05). In the ketoconazole group, the number of positive P. ovale cultures decreased from 60% to 31% (n=35) compared to the placebo group (64% to 56%; n=39). The clinical response was most significant in female patients with positive yeast cultures. CONCLUSION: Saprophytic yeasts may be a source of allergens in AD. Thus, patients with AD, yeast growth, and elevated IgE levels to yeasts should be offered antifungal treatment.

A multicenter study of patch test reactions with dental screening series.

BACKGROUND: Dental products contain many allergens, and may cause problems both for patients undergoing dental treatment and for dental personnel because of occupational exposure. Individual patch test clinics may not study sufficient numbers of patients to collect reliable data on uncommon allergens. OBJECTIVE: To collect information on dental allergens based on a multicenter study. MATERIALS AND METHODS: The Finnish Contact Dermatitis Group tested more than 4,000 patients (for most allergens, 2,300 to 2,600 patients) with dental screening series. Conventional patch testing was performed. The total number and percentage of irritant (scored as irritant [IR] or doubtful [?]) and allergic (scored as +, ++, or +++) patch test reactions, respectively, were calculated, as well as the highest and lowest percentage of allergic patch test reactions recorded by the different patch test clinics. A reaction index (RI) was calculated, giving information on the irritancy of the patch test substances. RESULTS: The most frequent allergic patch test reactions were caused by nickel (14.6%), ammoniated mercury (13%), mercury (10.3%), gold (7.7%), benzoic acid (4.3%), palladium (4.2%) and cobalt (4.1%). 2-hydroxyethyl methacrylate (2.8%) provoked most of the reactions caused by (meth)acrylates. Menthol, peppermint oil, ammonium tetrachloroplatinate, and amalgam alloying metals provoked no (neither allergic nor irritant) patch test reactions. CONCLUSION: Patch testing with allergens in the dental screening series, including (meth)acrylates and mercury, needs to be performed to detect contact allergy to dental products.

Prevalence of nickel allergy among Finnish university students in 1995.

Nickel allergy was studied in a sample of 1st-year university students starting their studies in 1995. A total of 296 subjects (72%) of 413 invited participated in the clinical examination, and 284, 96 male and 188 female, were patch tested (69%). A history of nickel sensitization was enquired for. Prick tests and serum specific IgE levels were determined. Occurrence of atopic dermatitis, hand eczema, and current exposure to metals were recorded. Nickel allergy was encountered in 39% of all female students, in 42% of females with pierced skin, and in 14% of females without pierced skin. The corresponding figures for males were 3%, 7% and 3%. In the multiple regression analysis, the risk factors for nickel allergy were female sex (OR 8.1, p<0.01), current metal exposure at examination (OR 4.1, p<0.01) and skin piercing (OR 3.6, p<0.05). Positive prick tests or elevated IgE levels to common allergens were not significantly associated with nickel allergy. In female students, the prevalence of nickel allergy has increased from 13% in 1986 to 39%. The prevalence among males has remained low at 3%. The results indicate that, in addition to skin piercing, current metal contacts are important risk factors for nickel allergy. This finding gives support to the EU Nickel Directive.

Pityrosporum and Candida specific and non-specific humoral, cellular and cytokine responses in atopic dermatitis patients.

BACKGROUND: Recent cytokine (RT-PCR, ELISA) analyses of inflammation in atopic dermatitis (AD) have suggested a role for IL-4, IL-5 and IFNgamma. Pityrosporum ovale and Candida albicans are important allergens in some patients with AD of the seborrhoic head, neck and shoulder region. In AD patients, the saprophytic yeasts induce IgE responses while they usually induce TH1 type responses. The cytokine responses induced by yeasts in AD are sparsely investigated. OBJECTIVE: To characterize the P. ovale- and C. albicans-specific and non-specific humoral, lymphoproliferative and cytokine (IL-2, 4, 5 and IFNgamma) responses in AD. METHODS: Fifteen AD patients and seven healthy controls (HC) were included. Ficoll-isolated PBMC were stimulated by PHA and laboratory-generated extracts of P. ovale and C. albicans. Lymphocyte proliferation was measured by 3H-thymidine incorporation and cytokine production by sandwich-ELISAs. The antigen-specific IgG and IgE antibodies were analysed by ELISA and nitrocellulose RAST. RESULTS: Pityrosporum ovale- and C. albicans-specific IgE (both P < 0.001) and P. ovale-induced PBMC proliferation (P < 0.02) were elevated in AD. In general, the IL-4/IFNgamma ratio induced by P. ovale was higher than that induced by C. albicans (P < 0.01). The PHA-induced IL-2 (P < 0.05) and IL-4 responses (P < 0.005), and the C. albicans-induced IL-5 response (P < 0.02) and IFNgamma response (P < 0.01), were elevated in AD. A network of correlations was seen between serum total and the yeast-specific IgE, P. ovale-specific lymphoproliferation, PHA-induced IL-2, IL-4 and IL-5, and C. albicans-induced IL-5. CONCLUSION: The cytokine profiles found in this study support the role of TH0 or TH1 cells by the side of TH2 cells in the pathogenesis of atopic dermatitis. Pityrosporum ovale appears to be associated more with IL-4 responses and C. albicans with IFNgamma responses.

Effect of dietary supplementation with sea buckthorn (Hippophaë rhamnoides) seed and pulp oils on the fatty acid composition of skin glycerophospholipids of patients with atopic dermatitis.

Sea buckthorn (Hippophaë rhamnoides) seed and pulp oils have traditionally been used for treating skin diseases in China and Russia, but are not widely used in other countries. A placebo-controlled, parallel study was carried out to investigate the effects of these oils on the fatty acid composition of skin glycerophospholipids of patients with atopic dermatitis. Sixteen patients ate 5 g of sea buckthorn seed oil, pulp oil, or paraffin oil daily for 4 months. Skin fatty acids were analyzed with gas chromatography before and after treatment. The seed oil slightly increased the proportion of docosapentaenoic acid (22:5n-3) and decreased the proportion of palmitic acid (16:0) in skin glycerophospholipids (0.05 < P < 0.1). The levels of the other fatty acids remained stable. The results show that the fatty acid composition of skin glycerophospholipids is well buffered against short-term dietary modification.

Antigliadin IgE--indicator of wheat allergy in atopic dermatitis.

BACKGROUND: Cereal grains are recognized as the cause of adverse reactions in some patients exposed to grain or flour by either inhalation or ingestion. Cereal-related diseases, such as celiac disease and baker's asthma, have been well studied and the causative cereal proteins have been characterized. Although cereals form an essential part of daily nutrition, the allergenic proteins causing symptoms on ingestion in atopic dermatitis (AD) have remained obscure. In this study, we have investigated the allergenic fraction of wheat in AD. METHODS: Skin prick tests (SPT) with a NaCl wheat suspension and the ethanol-soluble wheat gliadin were performed on 18 wheat-challenge-positive or -negative children with AD, six adult AD patients with suspected cereal allergy, and one adult with wheat-dependent exercise-induced urticaria/anaphylaxis. Serum total IgE and specific IgE-antibody levels to wheat and gluten were measured with the radioallergosorbent test (RAST) simultaneously. In addition serum samples of all 25 patients were analyzed by IgE immunoblotting with the ethanol-soluble wheat-protein extract. RESULTS: Thirteen of the AD children were wheat-challenge-positive, 11/12 of them appeared to be positive with gliadin SPT, and all had an elevated gluten RAST value. Those challenge-negative were negative with both gliadin SPT and gluten RAST. Positive wheat SPT and RAST alone were not associated with positive challenges. Four of the adult patients responded to a cereal-free diet, although only two of them appeared to be positive with gliadin SPT and gluten RAST. A broad and intensive staining of gliadin peptides in IgE-immunoblotting studies was seen in challenge-positive children with positive gliadin SPT and/ or gluten RAST. Besides staining of peptides in the main gliadin area of 30-46 kDa, a characteristic finding was the staining of small, <14-kDa proteins with sera of challenge- and gliadin-SPT-positive patients. CONCLUSIONS: We found that wheat-allergic AD patients have IgE antibodies against gliadin that can be detected by both SPT and the sensitive immunoblotting method. This suggests that gliadin peptides are important allergens, and ingestion of wheat causes symptoms of AD. A broad and intensive IgE staining was seen of gliadin peptides against both the previously characterized peptides in the main gliadin area and small, previously uncharacterized peptides of less than 14 kDa. The gliadin SPT and gluten RAST are good screening methods. Further characterization of the IgE-stained gliadin proteins is needed.

Cross-reacting IgE and IgG antibodies to Pityrosporum ovale mannan and other yeasts in atopic dermatitis.

Atopic dermatitis (AD) patients often demonstrate positive skin prick test results and serum IgE antibodies to a range of different yeasts. This has been thought to be due to cross-reactivity. In this study, the cross-reactivity of IgE and IgG antibodies between mannan and crude antigens of Pityrosporum ovale, Candida albicans, and Saccharomyces cerevisiae and crude antigens of Cryptococcus albidus and Rhodotorula rubra was examined by RAST and ELISA inhibition with two serum pools of AD patients. We found cross-reacting IgE and IgG antibodies. In the IgE response, the main cross-reacting pattern was the mannan region, although inhibition could be achieved also with crude antigens of C. albicans, S. cerevisiae, and, to some extent, C. albidus. P. ovale was the most potent inhibitor of IgE-binding components, and against it the highest IgE antibody levels were detected in AD serum pools. In contrast, C. albicans was found to be the most important inducer of IgG antibodies, since the IgG level against P. ovale mannan in both AD serum pools was very low. Cross-reacting antibodies were also seen in ELISA inhibition with both crude and mannan antigens, but since the IgG antibody level of P. ovale mannan in AD serum pools was low, further studies are needed to confirm the IgG results.