Use of oral immunosuppressive drugs in the treatment of atopic dermatitis in the Netherlands.

BACKGROUND: Although atopic dermatitis (AD) is a very common skin disease, data on the percentage of patients with really difficult-to-treat AD are scarce. From socio-economic perspective, it is important to have more insight into these numbers, as new very effective, but expensive, treatment options will be available in the near future for difficult-to-treat AD. Estimating the number of patients with AD using oral immunosuppressive drugs can give an impression of the percentage of difficult-to-treat patients in the total AD population. OBJECTIVE: To give an overview of the use of oral immunosuppressive drugs in patients with AD in the Netherlands. METHODS: Prescription data of oral immunosuppressive drugs in the Netherlands were extracted from a pharmaceutical database (NControl) containing data of 557 million prescriptions and 7.2 million patients. An algorithm, based on the WHO Anatomical Therapeutic Chemical (ATC) codes, was used to identify patients with AD. The prescription of oral immunosuppressive drugs in patients with AD between 1 January 2012 and 1 January 2017 was evaluated. RESULTS: Based on the algorithm, 65 943 patients with AD were selected. 943 patients with AD (1.4%) used cyclosporine A, methotrexate, azathioprine or mycophenolic acid. Methotrexate was most commonly used, followed by azathioprine and cyclosporine A. A switch in medication was rarely seen. In the evaluation period, a decrease in the prescription of cyclosporine A was seen, together with an increase in the prescription of methotrexate. In 31% of the patients who stopped treatment, the discontinuation took place within the first months of treatment. CONCLUSION: In this study population, 1.4% of the patients with AD used oral immunosuppressive drugs for their eczema in a 5-year period. Methotrexate was the most commonly used systemic drug in the Netherlands for the treatment of AD.

Is there an increased risk of cervical neoplasia in atopic dermatitis patients treated with oral immunosuppressive drugs?

BACKGROUND: Oral immunosuppressive drugs are frequently prescribed in young women with atopic dermatitis (AD). Immunocompromised patients may have a higher risk of developing high-risk HPV infections, cervical intra-epithelial neoplasia (CIN) and cervical carcinoma. Most literature on patients using oral immunosuppressive drugs is available in organ transplant patients. Literature on the risk of developing cervical carcinoma in AD patients treated with oral immunosuppressive drugs is lacking. At this moment, there is no clear guideline/consensus on this topic, but in daily practice, questions arise concerning whether this risk is increased and whether more intensive screening in women using immunosuppressive drugs should take place. OBJECTIVE: To investigate the occurrence of cervical carcinoma in women with AD treated with oral immunosuppressive drugs. METHODS: In this retrospective cohort study in two university medical centres in the Netherlands, all female adult AD patients receiving oral immunosuppressive drugs (cyclosporine A, azathioprine, methotrexate, mycophenolate mofetil, enteric-coated mycophenolate sodium and extended release tacrolimus) for more than 2 months between 1989 and 1 January 2014 were included. Patient files in the national histopathology register were screened for PAP3a, CIN I, CIN II, CIN III and cervical carcinoma. RESULTS: A total of 257 female AD patients with one or more treatment episodes from 1989 until 1 January 2014 were identified and included in this study. In 189 patients (73.5%), results of cervical examination were reported in the national histopathology database. Median total duration of treatment in these 189 women was 407.0 days (IQR 243.0-940.0). No cervical carcinoma during or following immunosuppressive therapy was found in our patient group. CONCLUSIONS: No intensified screening programme for cervical neoplasia seems necessary for women with AD using oral immunosuppressive drugs.

Effectiveness of alpine climate treatment for children with difficult to treat atopic dermatitis: Results of a pragmatic randomized controlled trial (DAVOS trial).

BACKGROUND: Alpine climate treatment has historically been used in Europe to treat atopic dermatitis (AD), but no randomized trials have been conducted to provide evidence for its effectiveness. OBJECTIVE: To investigate the long-term effectiveness of alpine climate treatment for children with difficult to treat AD. MATERIALS & METHODS: A pragmatic, open, randomized controlled trial was conducted. Children diagnosed with AD that was considered difficult to treat, aged between 8 and 18 years and willing to be treated in Switzerland were randomized to a six-week personalized integrative multidisciplinary treatment period in a clinical setting in the alpine climate (Switzerland) or an outpatient setting in moderate maritime climate (Netherlands). Study assessments were conducted at the Wilhelmina Children's Hospital; an electronic portal was used for the collection of questionnaire data. Primary outcomes were disease activity (SAEASI), quality of life (CDLQI) and catastrophizing thoughts (JUCKKI/JU) 6 months after intervention. Other assessments were immediately and 6 weeks after intervention. Subgroup analyses concerned asthma-related outcomes. Children were randomly assigned to either the intervention or control group using a covariate adaptive randomization method, taking age and asthma diagnosis into account. Children, parents and healthcare professionals involved in treatment were not blinded to group assignment. Data were analysed according to intention-to-treat with linear mixed-effects models for continuous outcomes. The trial is registered at Current Controlled Trials ISCRTN88136485. RESULTS: Between 14 September 2010 and 30 September 2014, 88 children were enrolled in the trial, 84 children were randomized (41 assigned to intervention, 43 to control) of whom 77 completed the intervention (38 of 41 (93%) intervention, 39 of 43 (91%) control) and 74 completed follow-up (38 of 41 (93%) intervention, 36 of 43 (84%) control). Six months after intervention there were no significant differences between the groups on disease activity (SAEASI mean difference -3.4 (95%CI -8.5 to 1.7)), quality of life (CDLQI mean difference -0.3 (95%CI -2.0 to 1.4)) and catastrophizing thoughts (JUCCKI/JU subscale mean difference -0.7 (95%CI -1.4 to -0.0)). Immediately and 6 weeks after intervention, disease activity and quality of life were significantly different in favour of alpine climate treatment. Mean differences on SAEASI were -10.1 (95%CI -14.5 to -5.8) and -8.4 (95%CI -12.2 to -4.6) and on CDLQI -1.9 (95%CI -3.3 to -0.5) and -1.5 (95%CI -2.8 to -0.3) immediately and 6 weeks after the intervention, respectively. There were no long-term differences on asthma-related outcomes. Five serious adverse events occurred during the study period, which were not thought to be related to the treatment. CONCLUSIONS & CLINICAL RELEVANCE: For children with difficult to treat AD, there was no additional long-term benefit of alpine climate treatment, in contrast to the short-term, compared to an outpatient treatment programme in moderate maritime climate, using a personalized integrative multidisciplinary treatment approach.

Thiopurine metabolite levels in patients with atopic dermatitis and/or chronic hand/foot eczema treated with azathioprine.

BACKGROUND: Azathioprine is frequently used in severe eczema. It is converted in the liver into active metabolites, including 6-thioguanine nucleotide (6-TGN) and methylated 6-methylmercaptopurine (6-MMP). In the past, the therapeutic potential of azathioprine may have not been fully utilized. Recent investigations on inflammatory bowel disease have led to a better understanding of azathioprine metabolism and optimizing treatment. OBJECTIVE: To investigate whether measuring thiopurine metabolites in circulation can improve the effectiveness and safety of azathioprine treatment in patients with atopic dermatitis and/or chronic hand/foot eczema. METHODS: Azathioprine metabolite levels were measured in eczema patients during maintenance treatment (Part I) and dose escalation (Part II). Clinical effectiveness, hepatotoxicity, and bone marrow suppression were analyzed and TPMT genotype was assessed. RESULTS: A wide variation in metabolite levels in all dose groups was observed. In Part I (32 patients), there were no significant differences in 6-TGN levels between clinical responders and non-responders (p = .806). No hepatoxicity or myelotoxicity was observed. In Part II, all 6-TGN and 6-MMP levels increased during dose escalation. Hypermethylation was observed in 2/8 patients. CONCLUSION: For individual eczema patients treated with azathioprine, routinely measuring 6-TGN and 6-MMP can be helpful in optimizing azathioprine dose, improving clinical effectiveness, and preventing side effects.

Atopic dermatitis characteristics and medication-use patterns in school-age children with AD and asthma symptoms.

BACKGROUND: Atopic dermatitis (AD) and asthma often coexist. Both diseases can have a major impact on the lives of children with AD and their caregivers. AIM: To investigate the association of patient characteristics, comorbidities and impact of AD on children who have both asthma and AD. METHODS: Children with AD (n = 140) were selected from a larger cohort of children with a reported use of asthma medication. The Children's Dermatology Life Quality Index (CDLQI) was used to assess Quality of Life (QoL), and the Self-Assessed Eczema Area and Severity Index (SA-EASI) was used to measure AD severity. Characteristics assessed included: age, sex, and the number and type of atopic comorbidities. Medication use for AD was defined using the total number of AD prescriptions, the number of different topical AD prescriptions and the highest potency topical corticosteroid (TCS) used. Determinants of AD severity and QoL were evaluated using Spearman rank tests. RESULTS: The following factors were most strongly associated with a lower QoL: characteristics of AD lesions (Spearman Rs = 0.61-0.69, P < 0.01), a higher SA-EASI score (Rs = 0.54, P < 0.01) and a larger number of different topical AD prescriptions (Rs = 0.38, P < 0.01). The following factors were correlated with more severe AD: age (Rs = -0.36, P < 0.01), larger number of different TCS preparations used (Rs = 0.27, P < 0.05) and larger number of TCS prescriptions (Rs = 0.25, P < 0.05). CONCLUSION: In children with asthma and AD, the number of TCS preparations used is associated with lower QoL and increased AD severity.

Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis.

Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93-80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage.

Immunoglobulin free light chains in adult atopic dermatitis patients do not correlate with disease severity.

BACKGROUND: Although total IgE levels have been proposed as a biomarker for disease severity in atopic dermatitis (AD) and are increased in the majority of AD patients, they do not correlate with disease severity during short-term follow-up. During the synthesis of immunoglobulins, free light chains (Ig-FLCs) are produced in excess over heavy chains. In comparison with IgE molecules, Ig-FLCs have a very short serum half-life. Therefore, Ig-FLCs might be more suitable as a biomarker for disease severity during follow-up. Recent studies showed increased serum levels of kappa Ig-FLCs in infants with AD, correlating with disease severity. The aim of this study was to investigate serum kappa Ig-FLC levels in adults with AD, and their correlation to disease severity. METHODS: Serum kappa If-FLC and total IgE levels were measured in 82 moderate to severe AD patients and 49 non-atopic controls. Blood was collected from patients before start of treatment with potent topical steroids (European classification: III-IV). 32 patients were treated during a clinical admission, and in this subpopulation a second blood sample was taken after 2 weeks of treatment. Clinical severity was determined by the Six Area Six Sign Atopic Dermatitis (SASSAD) severity score and a panel of serum biomarkers, including thymus and activation-regulated chemokine (TARC). RESULTS: Serum kappa Ig-FLCs levels in adult AD patients were not increased compared to non-atopic controls. Moreover, we observed no correlation between kappa Ig-FLC serum levels and disease severity determined by SASSAD and a panel of serum biomarkers, including TARC. Serum kappa Ig-FLC levels did also not decrease during treatment. CONCLUSION: There are no differences in serum kappa Ig-FLC levels between adult patients suffering from moderate to severe AD compared to non-atopic controls. Moreover, serum levels of kappa Ig-FLCs cannot be used as a biomarker for disease severity in adult AD.

Rush immunotherapy for wasp venom allergy seems safe and effective in patients with mastocytosis.

BACKGROUND: Patients with mastocytosis and wasp venom allergy (WA) may benefit from venom immunotherapy (VIT). However, fatal insect sting reactions have been described in mastocytosis patients despite previous immunotherapy. We investigated the safety and efficacy of (rush) VIT in patients with mastocytosis and WA. OBJECTIVE: To investigate the safety and efficacy of (rush) VIT in patients with mastocytosis and WA. METHODS: We describe nine patients with cutaneous mastocytosis and WA who received VIT. Cutaneous mastocytosis was confirmed by histopathology and systemic mastocytosis was diagnosed according to World Health Organization criteria. VIT was given according to a rush protocol. Given the difference in safety and efficacy of VIT in patients with WA and honeybee venom allergy, we reviewed the literature for VIT with the focus on WA patients with mastocytosis and addressed the difference between patients with cutaneous versus systemic mastocytosis. RESULTS: Nine patients had WA and mastocytosis, of whom six had cutaneous mastocytosis, two combined cutaneous and systemic mastocytosis and one systemic mastocytosis. All patients received rush IT with wasp venom. Most patients had only mild local side effects, with no systemic side effects during the course of VIT. One patient had a systemic reaction upon injection on one occasion, during the updosing phase, with dyspnoea and hypotension, but responded well to treatment. Immunotherapy was continued after temporary dose adjustment without problems. Two patients with a previous anaphylactic reaction were re-stung, without any systemic effects. CONCLUSIONS: VIT is safe in cutaneous mastocytosis patients with WA, while caution has to be made in case of systemic mastocytosis. VIT was effective in the patients who were re-stung.

Objective eliciting doses of peanut-allergic adults and children can be combined for risk assessment purposes.

BACKGROUND: To improve food labelling strategies, information regarding eliciting doses (EDs) and the effect of patient characteristics on these EDs is necessary. OBJECTIVE: To establish EDs for objective and subjective symptoms and analyse the effect of sensitization levels and other patient characteristics on threshold distribution curves (TDCs). METHODS: Threshold data from 100 adults and 262 children with a positive food challenge were analysed with interval-censoring survival analysis (ICSA) and fitted to a TDC from which EDs could be extracted. Possible influencing factors were analysed as covariates by ICSA. A hazard ratio (HR) was calculated in case of a significant effect. RESULTS: TDCs for both objective and subjective symptoms were significantly different between adults and children (P < 0.001). Objective ED05 values, however, were comparable (2.86 mg peanut protein in adults and 6.38 mg in children). Higher levels of sIgE to Ara h 2 and peanut extract were associated with a larger proportion of patient groups reacting to a dose increase with objective symptoms (adults and children) or subjective symptoms (adults, in children a trend). Age had a similar effect in children (HR 1.05 for objective symptoms and 1.09 for subjective symptoms). Gender had no effect on TDCs. CONCLUSION AND CLINICAL RELEVANCE: Subjective and objective TDCs were different between adults and children, but objective ED05 values were comparable, meaning that threshold data from children and adults can be combined for elaboration of reference doses for risk assessment. Higher sIgE levels to Ara h 2 and peanut extract were associated with a larger proportion of both patient groups to react to a certain dose increase.

Drug survival for ciclosporin A in a long-term daily practice cohort of adult patients with atopic dermatitis.

BACKGROUND: Long-term data of ciclosporin A (CsA) treatment in daily practice in patients with severe atopic dermatitis (AD) are lacking. OBJECTIVES: To perform a detailed analysis of drug survival, which is the length of time a patient continues to take a drug, for CsA in a long-term daily practice cohort of patients with AD. The secondary objective was to identify determinants of drug survival. METHODS: Data were extracted from a retrospective cohort of patients treated with CsA for AD. Drug survival was analysed using Kaplan-Meier survival curves. Determinants of drug survival were analysed using uni- and multivariate Cox regression analyses with backward selection. RESULTS: In total, 356 adult patients were analysed (386 patient-years). The overall drug survival rates were 34%, 18%, 12% and 4% after 1, 2, 3 and 6 years, respectively. Reasons for discontinuation were controlled AD (26·4%), side-effects (22·2%), ineffectiveness (16·3%), side-effects plus ineffectiveness (6·2%) or other reasons (11·0%). Older age was associated with a decreased drug survival related to controlled AD [hazard ratio (HR) 0·91]. Older age was also associated with a decreased drug survival related to side-effects (HR 1·14). An intermediate-to-high starting dose (> 3·5-5·0 mg kg(-1) daily) was associated with an increased drug survival related to ineffectiveness (HR 0·63). CONCLUSIONS: This is the first study on drug survival for CsA treatment in AD. Older age was associated with decreased drug survival related to controlled AD and side-effects. An intermediate-to-high starting dose was associated with an increased drug survival related to ineffectiveness.

Diagnostic accuracy of specific IgE to components in diagnosing peanut allergy: a systematic review.

The diagnostic accuracy of skin prick test (SPT) and specific IgE (sIgE) to peanut extract in diagnosing peanut allergy is suboptimal. Recent studies have evaluated sIgE to peanut components as a possible new diagnostic tool. The aim of our review was to systematically search the literature to assess the diagnostic value of sIgE to peanut components in diagnosing peanut allergy. A literature search was performed in PubMed, Embase and the Cochrane Library. Results were subsequently screened for in- and exclusion criteria. The quality of eligible studies was assessed using a standardized quality assessment tool (QUADAS-2). Data on sensitivity, specificity, and positive and negative likelihood ratios were extracted or calculated for a descriptive analysis. Twenty-two studies were eligible, of which 21 studies in paediatric populations. Most studies reported on sIgE to peanut extract (15) and sIgE to Ara h 2 (12), followed by SPT (9) and sIgE to Ara h 1 (7). All studies were at risk of bias or caused applicability concerns on at least one item of the quality assessment tool. The best combination of diagnostic accuracy measures of all diagnostic tests was found for sIgE to Ara h 2. This finding was independent of geographical location. Compared to SPT and sIgE to peanut extract, sIgE to Ara h 2 was mainly superior in diagnosing peanut allergy in case of a positive test result. Worst diagnostic accuracy measures were found in general for sIgE to Ara h 8 and sIgE to Ara h 9. sIgE to Ara h 2 showed the best diagnostic accuracy of all diagnostic tests to diagnose peanut allergy. Compared to the currently used SPT and sIgE to peanut extract, sIgE to Ara h 2 was superior in diagnosing peanut allergy and should therefore replace these tests in daily clinical practice, especially in children.

A national study on adherence to a basal cell carcinoma guideline; development of a tool to assess guideline adherence.

BACKGROUND: Clinical practice guideline implementation may be at variance with actual daily practice, as guideline adherence is a complex process depending on many actors and factors. Feedback regarding adherence is essential to monitor the effect that a guideline has in clinical practice and whether or not the quality of care is raised by implementation. OBJECTIVES: Developing a tool for obtaining and giving nationwide feedback regarding adherence. METHODS: From February 2010 to June 2013, a 32-item questionnaire was used as an audit tool during committee visits to assess adherence across 37 dermatological centres in The Netherlands. The questions were derived from the recommendations by the Dutch Dermatological and Venereological Society (NVDV) in the Dutch Basal Cell Carcinoma (BCC) guideline. Five selected medical records per dermatologist were audited and the results were discussed with the audited centre. Data were pooled to calculate the compliance with each recommendation across all participating centres. RESULTS: Adherence to recommended actions varied considerably (20·2-100%) across the domains of prevention, diagnostics, treatments and aftercare. Using and reporting surgical margins, giving patient advice, restricting the use of cryosurgery for certain BCCs and reporting on prognostic factors all failed to reach a threshold of 80%. Nonadherence to recommended actions proved to be related to whether or not a dermatologist was directly involved. CONCLUSIONS: The findings emphasize the importance of direct feedback to practitioners regarding adherence. Furthermore, together with existing frameworks, the method described could be used by developers in a guideline update to identify and anticipate barriers to successful implementation.

The diagnostic accuracy of specific IgE to Ara h 6 in adults is as good as Ara h 2.

Specific IgE (sIgE) to Ara h 2 is useful in diagnosing peanut allergy. Our aim was to assess the diagnostic value of sIgE to Ara h 6, another 2S albumin, in an adult population suspected of peanut allergy. Subjects with suspected peanut allergy between 2002 and 2013 were included if a diagnostic double-blind, placebo-controlled food challenge with peanut was performed. sIgE to Ara h 2 and Ara h 6 was measured by ImmunoCAP ISAC 112. Of 107 challenged subjects, 65 had a positive challenge (61%). The discriminative ability of sIgE to Ara h 2 and Ara h 6 was comparable: AUC 0.81 vs. 0.82. Positive predictive value for both tests was 95% using a cutoff value ≥1 ISU/l with poor corresponding sensitivity values (58% for Ara h 2, 62% for Ara h 6), but good specificity values (95% for both tests). In conclusion, the diagnostic value of sIgE to Ara h 6 on population level was as good as sIgE to Ara h 2. On individual level, however, 5% of the subjects showed contradicting results between both tests using a cutoff of 0.3 ISU/l, leading to a risk of misdiagnosis if only one of both tests is used.

The degree of whey hydrolysis does not uniformly affect in vitro basophil and T cell responses of cow's milk-allergic patients.

BACKGROUND: Several studies investigated whether hydrolysed proteins can induce tolerance to cow's milk (CM) in children at risk of developing CM allergy. Due to methodological problems and inconsistent findings, the evidence for a tolerogenic effect is limited. A major problem is that different hydrolysates may give different outcomes due to variations in their production and composition. OBJECTIVE: The aim of the study was to investigate the effect of the degree of hydrolysis on the allergenicity and immunogenicity of whey hydrolysates. METHODS: The hydrolysis of whey was stopped at different time-points between 1 and 60 min. In 18 CM allergic patients, the allergenicity of the hydrolysates was determined by immunoblot and the basophil activation test. To test immunogenicity, CM-specific T cell lines were generated. RESULTS: In most patients, increasing time of hydrolysis decreased IgE recognition and basophil activation. However, in five patients, hydrolysed proteins induced more basophil activation than non-hydrolysed proteins. The immunoblot data indicated that these patients recognized either a 25- to 30-kDa degradation product of casein or a 10-kDa degradation product of whey. Although T cell activation was decreased in all patients over time, half of them still showed a positive response to the proteins after 60 min of hydrolysis. CONCLUSION: Increasing the time of hydrolysis reduces both allergenicity and immunogenicity of whey hydrolysates in most but not all patients. This indicates that not the degree of hydrolysis is decisive but the presence and stability of IgE and T cell epitopes in the hydrolysate recognized by individual patients.

Components in soy allergy diagnostics: Gly m 2S albumin has the best diagnostic value in adults.

BACKGROUND: Thus far, four soy allergens have been characterized. Their diagnostic value was assessed only using a case-control design with controls not suspected of soy allergy or in a soy-allergic population without controls. Our objective was to analyze the diagnostic value of specific immunoglobulin E (sIgE) to Gly m 2S albumin, Gly m 4, 5, and 6, and their possible relation with severity or culprit soy product. METHODS: Adult patients suspected of soy allergy were included (n = 46). Allergy was confirmed by challenge (n = 19) or history (n = 16) and excluded by challenge in 11 patients. Soy components were analyzed by ImmunoCAP. Diagnostic value was assessed in the challenged patient group by an area under receiver operating characteristic (ROC) curve (AUC). RESULTS: Specific immunoglobulin E to Gly m 2S albumin had the highest AUC (0.79), comparable to skin prick test (SPT) and sIgE to soy extract (0.76 and 0.77, respectively). All patients were sensitized to either soy extract or Gly m 4 (sIgE ≥ 0.35 kU/l). sIgE to soy extract, Gly m 5, and Gly m 6 was significantly higher in patients with mild symptoms (P = 0.04, 0.02 and 0.02, respectively). Patients only reacting to soy milk had higher sIgE levels to Gly m 4 (median 9.8 vs 1.1 kU/l, P = 0.01). CONCLUSION: Specific immunoglobulin E to Gly m 2S albumin had the best accuracy in diagnosing soy allergy. Gly m 5 and 6 were related to mild symptoms. Higher levels of Gly m 4 were related to allergy to soy milk.