Gamma-linolenic acid levels correlate with clinical efficacy of evening primrose oil in patients with atopic dermatitis.

INTRODUCTION Atopic dermatitis (AD) has been related to a deficiency of delta-6-desaturase, an enzyme responsible for the conversion of linoleic acid to gamma-linolenic acid (GLA). Evening primrose oil (EPO) contains high amounts of GLA. Therefore, this study investigated whether EPO supplementation results in an increase in plasma GLA and its metabolite dihomo-gamma-linolenic acid (DGLA) correlating with clinical improvement of AD, assessed by the SCORing Atopic Dermatitis (SCORAD) index. METHODS The open study included 21 patients with AD. EPO (4-6 g) was administered daily for 12 weeks. Before treatment, and 4 and 12 weeks after initiation of EPO supplementation, objective SCORAD was assessed and plasma concentrations of GLA and DGLA were determined by gas chromatography. RESULTS A significant increase in plasma GLA and DGLA levels and a decrease in the objective SCORAD were observed 4 and 12 weeks after initiation of EPO treatment. In the per-protocol population (n = 14), a significant inverse correlation between the changes in plasma GLA levels and SCORAD was found (P = 0.008). CONCLUSION The clinical disease activity under EPO treatment correlates with the individual increase in plasma GLA levels. Thus, the results of this pilot study indicate that an increase in plasma GLA might be used as predictive parameter for responsiveness of AD to EPO therapy.

Systemic therapy for atopic dermatitis.

Systemic therapy for atopic dermatitis (AD) is indicated in patients with severe disease refractory to adequate topical treatment. Currently available drugs aim to decrease inflammation by suppressing and/or modulating immune responses and thus may indirectly improve skin barrier function, resulting in a decrease in clinical signs and symptoms in particular pruritus. Before considering systemic treatment, patient adherence to topical treatment including skin care has to be ensured. The selection of the drug depends on the disease severity, localization, complications, concomitant diseases, and age of the patient, but also on their availability and costs as well as the doctor's experience. Bearing in mind the potential risk of resistance, systemic therapy with antibiotics should be exclusively considered in clinically manifest infections such as in children. Here, we review recently published clinical trials and case reports on systemic therapy of pediatric and adult patients with AD to draw conclusions for clinical practice. Although AD is a common disease, controlled clinical studies investigating the efficacy of systemic drugs are scarce, except for cyclosporine, which has been approved for the therapy of severe AD.

Transcriptional analysis of left-sided colitis, pancolitis, and ulcerative colitis-associated dysplasia.

BACKGROUND It is unknown why patients with extensive ulcerative colitis (UC) have a higher risk of colorectal cancer compared with patients with left-sided UC. This study characterizes the inflammatory processes in left-sided UC, pancolitis, and UC-associated dysplasia at the transcriptional level to identify potential biomarkers and transcripts of importance for the carcinogenic behavior of chronic inflammation. METHODS The Affymetrix GeneChip Human Genome U133 Plus 2.0 was applied on colonic biopsies from UC patients with left-sided UC, pancolitis, dysplasia, and controls. Reverse transcription polymerase chain reaction and immunohistochemistry were performed for validating selected transcripts in the initial cohort and in 2 independent cohorts of patients with UC. Microarray data were analyzed by principal component analysis, and reverse transcription polymerase chain reaction and immunohistochemistry data by the Wilcoxon's rank-sum test. RESULTS The principal component analysis results revealed separate clusters for left-sided UC, pancolitis, dysplasia, and controls. Close clustering of dysplastic and pancolitic samples indicated similarities in gene expression. Indeed, 101 and 656 parallel upregulated and downregulated transcripts, respectively, were identified in specimens from dysplasia and pancolitis. Validation of selected transcripts hereof identified insulin receptor alpha (INSRA) and MAP kinase interacting serine/threonine kinase 2 (MKNK2) with an enhanced expression in dysplasia compared with left-sided UC and controls, whereas laminin γ2 (LAMC2) was found with a lower expression in dysplasia compared with the remaining 3 groups. CONCLUSIONS This study demonstrates pancolitis and left-sided UC as distinct inflammatory processes at the transcriptional level, and identifies INSRA, MKNK2, and LAMC2 as potential critical transcripts in the inflammation-driven preneoplastic process of UC.

Use of activity monitors for assessment of pruritus in an acute model of canine atopic dermatitis

BACKGROUND: We developed a canine model of acute atopic dermatitis to evaluate the potential of compounds to treat pruritus and skin lesions induced in Dermatophagoides farinae (Df)-sensitized dogs. HYPOTHESIS/OBJECTIVES: The aim was to investigate the effectiveness of long-term recording activity monitors to assess pruritus induced by allergen challenges. ANIMALS: Thirty-two Df-sensitized laboratory dogs. METHODS: In two blinded crossover studies, 28 Df-sensitized dogs were challenged on 3 days with a Df slurry applied to clipped abdominal skin. Dogs were treated with a positive control (prednisolone 1 mg/kg once daily for 5 days, starting 1 day before challenge) or left untreated; all were fitted with activity monitors. To confirm pruritus, a parallel study with four dogs was conducted, filming the dogs before and during challenge and assessing the film for pruritic behaviour. RESULTS: The activity of dogs treated with prednisolone was significantly lower between 00.00 and 03.00 h and between 03.00 and 06.00 h compared with untreated dogs (repeated-measures ANCOVA; P < 0.0001). To determine whether the recorded night-time activity corresponded to pruritic manifestations, we compared activity monitor and video recordings of four dogs for two periods (16.30-20.30 and 24.00-03.00 h) before and during a Df challenge. The correlation between night-time activity monitor activity and observed pruritic behaviour was highly significant (test of correlation coefficient versus zero: r = 0.57, P < 0.0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Determination of night-time activity with activity monitors after allergen challenge appears to be an objective and practical way to assess pruritus in this experimental model of canine atopic dermatitis.

Appropriateness and long-term discontinuation rate of biological therapies in ulcerative colitis

BACKGROUND Anti-TNFα agents are commonly used for ulcerative colitis (UC) therapy in the event of non-response to conventional strategies or as colon-salvaging therapy. The objectives were to assess the appropriateness of biological therapies for UC patients and to study treatment discontinuation over time, according to appropriateness of treatment, as a measure of outcome. METHODS We selected adult ulcerative colitis patients from the Swiss IBD cohort who had been treated with anti-TNFα agents. Appropriateness of the first-line anti-TNFα treatment was assessed using detailed criteria developed during the European Panel on the Appropriateness of Therapy for UC. Treatment discontinuation as an outcome was assessed for categories of appropriateness. RESULTS Appropriateness of the first-line biological treatment was determined in 186 UC patients. For 64% of them, this treatment was considered appropriate. During follow-up, 37% of all patients discontinued biological treatment, 17% specifically because of failure. Time-to-failure of treatment was significantly different among patients on an appropriate biological treatment compared to those for whom the treatment was considered not appropriate (p=0.0007). Discontinuation rate after 2years was 26% compared to 54% between those two groups. Patients on inappropriate biological treatment were more likely to have severe disease, concomitant steroids and/or immunomodulators. They were also consistently more likely to suffer a failure of efficacy and to stop therapy during follow-up. CONCLUSION Appropriateness of first-line anti-TNFα therapy results in a greater likelihood of continuing with the therapy. In situations where biological treatment is uncertain or inappropriate, physicians should consider other options instead of prescribing anti-TNFα agents.

Nonthymoma-associated exfoliative dermatitis in 18 cats.

BACKGROUND Exfoliative dermatitis has been described in cats as a paraneoplastic skin disease associated with thymoma. There are anecdotal reports of cases without thymoma, with various suspected aetiologies. HYPOTHESIS/OBJECTIVES To identify common features, underlying causes, response to therapy and outcome of nonthymoma-associated exfoliative dermatitis in cats. METHODS Retrospective analysis was carried out of cases presented to dermatology referral centres or cases submitted for histopathological examination. Detailed historical and clinical data were obtained and evaluated statistically. Histopathology was reviewed in a blinded fashion by three dermatopathologists, and PCR for herpesvirus was performed. RESULTS Eighteen cats fulfilled all inclusion criteria. There was no sex, age or breed predisposition. All cats presented with severe generalized (77%) or multifocal exfoliation (23%); 12 cats were severely depressed. In all cats, thymoma was excluded radiographically and feline leukaemia virus tests were negative. Additional imaging procedures in 14 cats and postmortem examination in two cats did not detect neoplasia. Histopathology revealed interface dermatitis, mural interface folliculitis and sebaceous adenitis indistinguishable from findings in thymoma-associated cases. PCR for herpes DNA was negative. No aetiology was identified. Treatment in 12 cases consisted of immunosuppressive doses of corticosteroids and/or ciclosporin; one responded to antibiotics, one to shampoo, two went into spontaneous remission, and two did not receive any therapy and were euthanized. CONCLUSIONS AND CLINICAL IMPORTANCE Nonthymoma-associated exfoliative dermatitis in cats is clinically and histopathologically indistinguishable from thymoma-associated cases. Most cases benefit from immunosuppressive therapy; therefore, an immunopathological response to an undefined trigger is suspected.

The effectiveness and safety of rescue treatments in 108 patients with steroid-refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients

BACKGROUND: Among patients with steroid-refractory ulcerative colitis (UC) in whom a first rescue therapy has failed, a second line salvage treatment can be considered to avoid colectomy. AIM: To evaluate the efficacy and safety of second or third line rescue therapy over a one-year period. METHODS: Response to single or sequential rescue treatments with infliximab (5mg/kg intravenously (iv) at week 0, 2, 6 and then every 8weeks), ciclosporin (iv 2mg/kg/daily and then oral 5mg/kg/daily) or tacrolimus (0.05mg/kg divided in 2 doses) in steroid-refractory moderate to severe UC patients from 7 Swiss and 1 Serbian tertiary IBD centers was retrospectively studied. The primary endpoint was the one year colectomy rate. RESULTS: 60% of patients responded to the first rescue therapy, 10% went to colectomy and 30% non-responders were switched to a 2(nd) line rescue treatment. 66% of patients responded to the 2(nd) line treatment whereas 34% failed, of which 15% went to colectomy and 19% received a 3(rd) line rescue treatment. Among those, 50% patients went to colectomy. Overall colectomy rate of the whole cohort was 18%. Steroid-free remission rate was 39%. The adverse event rates were 33%, 37.5% and 30% for the first, second and third line treatment respectively. CONCLUSION: Our data show that medical intervention even with 2(nd) and 3(rd) rescue treatments decreased colectomy frequency within one year of follow up. A longer follow-up will be necessary to investigate whether sequential therapy will only postpone colectomy and what percentage of patients will remain in long-term remission.

Novel Nonbiologic Therapies for Ulcerative Colitis

An extensive array of compounds has been studied for the treatment of ulcerative colitis (UC). The most frequently used nonbiologic drugs for the oral and intravenous treatment of ulcerative colitis include 5-aminosalicylate (5-ASA) drugs (mesalamine and derivatives), sulfasalazine, and other azo-bonded molecules of 5-ASA, steroids, calcineurin inhibitors (cyclosporine, tacrolimus, and sirolimus), thiopurines (azathioprine, 6-mercaptopurine), and methotrexate, which are already presented in other sections of this book and are thus not considered in this chapter. The therapies presented in this section should be considered as potential alternatives, mostly for mild-to-moderate ulcerative colitis (UC). They are substances mostly used without FDA indications, such as heparin, nicotine, rosiglitazone, and N-acetylcysteine as well as “natural” compounds suggested to have anti-inflammatory or reparative properties, such as aloe vera, curcumin, short-chain fatty acids, and Bowman-Birk inhibitor

miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis

BACKGROUND Longstanding ulcerative colitis (UC) bears a high risk for development of UC-associated colorectal carcinoma (UCC). The inflammatory microenvironment influences microRNA expression, which in turn deregulates target gene expression. microRNA-26b (miR-26b) was shown to be instrumental in normal tissue growth and differentiation. Thus, we aimed to investigate the impact of miR-26b in inflammation-associated colorectal carcinogenesis. METHODS Two different cohorts of patients were investigated. In the retrospective group, a tissue microarray with 38 samples from 17 UC/UCC patients was used for miR-26b in situ hybridization and quantitative reverse transcription polymerase chain reaction analyses. In the prospective group, we investigated miR-26b expression in 25 fresh-frozen colon biopsies and corresponding serum samples of 6 UC and 15 non-UC patients, respectively. In silico analysis, Ago2-RNA immunoprecipitation, luciferase reporter assay, quantitative reverse transcription polymerase chain reaction examination, and miR-26b mimic overexpression were employed for target validation. RESULTS miR-26b expression was shown to be upregulated with disease progression in tissues and serum of UC and UCC patients. Using miR-26b and Ki-67 expression levels, an UCC was predicted with high accuracy. We identified 4 novel miR-26b targets (DIP1, MDM2, CREBBP, BRCA1). Among them, the downregulation of the E3 ubiquitin ligase DIP1 was closely related to death-associated protein kinase stabilization along the normal mucosa-UC-UCC sequence. In silico functional pathway analysis revealed that the common cellular pathways affected by miR-26b are highly related to cancerogenesis and the development of gastrointestinal diseases. CONCLUSIONS We suggest that miR-26b could serve as a biomarker for inflammation-associated processes in the gastrointestinal system. Because miR-26b expression is downregulated in sporadic colon cancer, it could discriminate between UCC and the sporadic cancer type.

Prevalence and Risk Factors for Therapy Escalation in Ulcerative Colitis in the Swiss IBD Cohort Study.

BACKGROUND Physicians traditionally treat ulcerative colitis (UC) using a step-up approach. Given the paucity of data, we aimed to assess the cumulative probability of UC-related need for step-up therapy and to identify escalation-associated risk factors. METHODS Patients with UC enrolled into the Swiss IBD Cohort Study were analyzed. The following steps from the bottom to the top of the therapeutic pyramid were examined: (1) 5-aminosalicylic acid and/or rectal corticosteroids, (2) systemic corticosteroids, (3) immunomodulators (IM) (azathioprine, 6-mercaptopurine, methotrexate), (4) TNF antagonists, (5) calcineurin inhibitors, and (6) colectomy. RESULTS Data on 996 patients with UC with a median disease duration of 9 years were examined. The point estimates of cumulative use of different treatments at years 1, 5, 10, and 20 after UC diagnosis were 91%, 96%, 96%, and 97%, respectively, for 5-ASA and/or rectal corticosteroids, 63%, 69%, 72%, and 79%, respectively, for systemic corticosteroids, 43%, 57%, 59%, and 64%, respectively, for IM, 15%, 28%, and 35% (up to year 10 only), respectively, for TNF antagonists, 5%, 9%, 11%, and 12%, respectively, for calcineurin inhibitors, 1%, 5%, 9%, and 18%, respectively, for colectomy. The presence of extraintestinal manifestations and extended disease location (at least left-sided colitis) were identified as risk factors for step-up in therapy with systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and surgery. Cigarette smoking at diagnosis was protective against surgery. CONCLUSIONS The presence of extraintestinal manifestations, left-sided colitis, and extensive colitis/pancolitis at the time of diagnosis were associated with use of systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and colectomy during the disease course.

Systematic analysis of factors associated with progression and regression of ulcerative colitis in 918 patients.

BACKGROUND Studies that systematically assess change in ulcerative colitis (UC) extent over time in adult patients are scarce. AIM To assess changes in disease extent over time and to evaluate clinical parameters associated with this change. METHODS Data from the Swiss IBD cohort study were analysed. We used logistic regression modelling to identify factors associated with a change in disease extent. RESULTS A total of 918 UC patients (45.3% females) were included. At diagnosis, UC patients presented with the following disease extent: proctitis [199 patients (21.7%)], left-sided colitis [338 patients (36.8%)] and extensive colitis/pancolitis [381 (41.5%)]. During a median disease duration of 9 [4-16] years, progression and regression was documented in 145 patients (15.8%) and 149 patients (16.2%) respectively. In addition, 624 patients (68.0%) had a stable disease extent. The following factors were identified to be associated with disease progression: treatment with systemic glucocorticoids [odds ratio (OR) 1.704, P = 0.025] and calcineurin inhibitors (OR: 2.716, P = 0.005). No specific factors were found to be associated with disease regression. CONCLUSIONS Over a median disease duration of 9 [4-16] years, about two-thirds of UC patients maintained the initial disease extent; the remaining one-third had experienced either progression or regression of the disease extent.

Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology

In this consensus document we summarize the current knowledge on major asthma, rhinitis, and atopic dermatitis endotypes under the auspices of the PRACTALL collaboration platform. PRACTALL is an initiative of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology aiming to harmonize the European and American approaches to best allergy practice and science. Precision medicine is of broad relevance for the management of asthma, rhinitis, and atopic dermatitis in the context of a better selection of treatment responders, risk prediction, and design of disease-modifying strategies. Progress has been made in profiling the type 2 immune response-driven asthma. The endotype driven approach for non-type 2 immune response asthma, rhinitis, and atopic dermatitis is lagging behind. Validation and qualification of biomarkers are needed to facilitate their translation into pathway-specific diagnostic tests. Wide consensus between academia, governmental regulators, and industry for further development and application of precision medicine in management of allergic diseases is of utmost importance. Improved knowledge of disease pathogenesis together with defining validated and qualified biomarkers are key approaches to precision medicine.

Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs.

BACKGROUND Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2. RESULTS Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27:19,086,778 (p = 1.4 × 10(-7)) and a rare ~48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the ~48 kb risk haplotype) that spanned ~280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 × 10(-5)), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27:19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region. CONCLUSIONS Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.