Recessive mosaicism in ABCA12 causes blaschkoid congenital ichthyosiform erythroderma.

We report the unique case of a 3-year-old girl who presented with linear erythematosquamous lesions following the lines of Blaschko, suggestive of genetic mosaicism in the skin. Single-candidate gene analyses were performed on DNA from blood, excluding Conradi-Hünermann-Happle syndrome, erythrokeratodermia variabilis and a mosaic presentation of pityriasis rubra pilaris. With whole-exome sequencing (WES) on DNA from the patient's blood, a heterozygous missense mutation in exon 25 of the ABCA12 gene was detected. By manually scrutinizing the WES data, another low-percentage pathogenic frameshift mutation was found in the adjacent exon 26 of the same gene. This frameshift mutation was confirmed with Sanger sequencing in DNA isolated from a lesional skin biopsy. A subsequent cloning experiment was performed to prove that the patient is compound heterozygous for both mutations in the affected skin, explaining the blaschkoid ichthyosiform erythrodermic phenotype. The patient's phenotype was elucidated by the combination of a germline mutation and an acquired postzygotic mutation in ABCA12, resulting in the diagnosis of a mosaic manifestation of autosomal recessive congenital ichthyosis. Postzygotic compound allelic loss in autosomal recessive disorders is extremely rare and will not appear as the typical phenotype of the known germline mutation-associated disease. This is the first report of a proven biallelic mosaic presentation of an autosomal recessive genodermatosis, and we propose the term 'recessive mosaicism' for this kind of manifestation. What's already know about this topic? Specific mutations in the ABCA12 lipid transporter are known to cause different phenotypes like harlequin ichthyosis, congenital ichthyosiform erythroderma and lamellar ichthyosis. In mosaicism, two or more cell populations that are genetically different arise postzygotically in the developing embryo. In the skin, mosaicism can present itself in different patterns of affected skin, often caused by a dominant genetic mutation. What does this study add? We report a unique patient with blaschkoid congenital ichthyosiform erythroderma due to biallelic mutations, one inherited germline missense mutation and the other a postzygotic frameshift mutation in the ABCA12 gene. This study describes the diagnostic approach and applied research that can be used if one encounters a similar diagnostic dilemma with manifestations suspected for genetic mosaicism. We propose the term 'recessive mosaicism' for this kind of mosaic presentation of an autosomal recessive genodermatosis.

The identification of CCL18 as biomarker of disease activity in localized scleroderma.

BACKGROUND: Localized Scleroderma (LoS) encompasses a group of idiopathic skin conditions characterized by (sub)cutaneous inflammation and subsequent development of fibrosis. Currently, lack of accurate tools enabling disease activity assessment leads to suboptimal treatment approaches. OBJECTIVE: To investigate serum concentrations of cytokines and chemokines implicated in inflammation and angiogenesis in LoS and explore their potential to be utilized as biomarker of disease activity. Additionally, to investigate the implication of potential biomarkers in disease pathogenesis. METHODS: A 39-plex Luminex immuno-assay was performed in serum samples of 74 LoS and 22 Healthy Controls. The relation between a validated clinical measure of disease activity (mLoSSI) and serum analytes was investigated. Additionally, gene and protein expression were investigated in circulating cells and skin biopsies. RESULTS: From the total of 39, 10 analytes (CCL18, CXCL9, CXCL10, CXCL13, TNFRII, Galectin-9, TIE-1, sVCAM, IL-18, CCL19) were elevated in LoS serum. Cluster analysis of serum samples revealed CCL18 as most important analyte to discriminate between active and inactive disease. At individual patient level, CCL18 serum levels correlated strongest with mLoSSI-scores (rs = 0.4604, P < 0.0001) and in longitudinal measures CCL18 concentrations normalised with declining disease activity upon treatment initiation. Additionally, CCL18 was elevated in LoS serum, and not in (juvenile) dermatomyositis or spinal muscular atrophy. Importantly, CCL18 gene and protein expression was increased at the inflammatory border of cutaneous LoS lesions, with normal expression in unaffected skin and circulating immune cells. CONCLUSION: CCL18 is specific for disease activity in LoS thereby providing relevance as a biomarker for this debilitating disease.

Polymorphisms in CD84, IL12B and TNFAIP3 are associated with response to biologics in patients with psoriasis.

BACKGROUND: The effectiveness of biologics for psoriasis shows heterogeneity among patients. With pharmacogenetic markers, it might be possible to predict treatment response. OBJECTIVES: We aimed to test the association between genetic markers and the response to biologics in psoriasis (etanercept, adalimumab, ustekinumab) in a prospective cohort. METHODS: We investigated the copy number variation in the LCE3B and LCE3C genes, and eight single-nucleotide polymorphisms (SNPs) in HLA-C*06, CD84, IL12B, IL23R, TRAF3IP2, ERAP1, IFIH1 and TNFAIP3. The decrease in Psoriasis Area and Severity Index (PASI) was calculated as ∆PASI (absolute PASI decrease compared with baseline) and PASI 75 (proportion of patients with ≥ 75% improvement vs. baseline). Associations between genetic variants and treatment outcome were assessed using multivariable linear regression analysis (∆PASI corrected for baseline PASI, primary analysis) and Pearson's χ2 -test or Fisher's exact test (PASI 75, secondary analysis). RESULTS: We included 348 treatment episodes in 234 patients. Patients heterozygous (GA) for the SNP in CD84 (rs6427528) had a better ∆PASI response to etanercept after 3 months (P = 0·025) than the homozygous reference group (GG). In addition, patients heterozygous (CT) for the IL12B variant showed a better response (∆PASI) to ustekinumab (P = 0·017) than the reference group (CC). Patients homozygous (GG) for the SNP in TNFAIP3 showed a worse response (∆PASI) to ustekinumab (P = 0·031) than the reference group (TT). The associations with ustekinumab resulting from the primary analysis were not confirmed in the secondary (PASI 75) analysis. CONCLUSIONS: We demonstrated a strong association between etanercept use in psoriasis and variations in CD84, a gene that was previously found to be a predictor of response to etanercept in rheumatoid arthritis.

Clearing of psoriasis documented by laser Doppler perfusion imaging contrasts remaining elevation of dermal expression levels of CD31.

BACKGROUND: Vascular modifications represent a key feature in psoriatic plaques. Previous research with Laser Doppler Perfusion Imaging (LDPI) revealed a remarkable heterogeneity in the cutaneous perfusion within homogenous-appearing psoriatic lesions. Insights in the relation between perfusion during treatment and related biological changes are lacking. OBJECTIVES: To study the effect of calcipotriol-betamethasone dipropionate ointment on the microcirculation and the expression levels of immunohistochemical markers in psoriatic lesions compared to the distant uninvolved skin. METHODS: Psoriatic lesions of fourteen patients were treated once a day during 8 weeks. Clinical SUM scores and the perfusion intensity by means of LDPI were assessed every 2 weeks. After 8 weeks, a biopsy from the target lesion and one from the distant uninvolved skin were taken and stained for psoriasis-related markers, like IL-17 and CD31. RESULTS: After 8 weeks, seven patients reached a SUM score of 0 or 1, and were classified as good-responders. The other patients were classified moderate-responders. The perfusion intensity decreased in all lesions during therapy. In the good-responders, all investigated psoriasis-related proteins within the treated lesions reached the expression level found within the distant uninvolved skin. The expression of CD31, however, was significantly higher in the treated lesions as compared to the distant uninvolved skin (p = 0.0156). In the moderate responders, almost all expression levels remained significantly elevated compared to the uninvolved skin. CONCLUSIONS: In the skin of good-responders the expression of dermal CD31(+) endothelium remains significantly elevated within the treated lesions compared with the distant uninvolved skin, whereas a marked reduction in the perfusion intensity and SUM score was found. This indicates that clinical improvement might outrun endothelial changes.

'Happy' drug survival of adalimumab, etanercept and ustekinumab in psoriasis in daily practice care: results from the BioCAPTURE network.

BACKGROUND: Drug survival is a marker for treatment success. To date, no analyses relating dermatological quality-of-life measures to drug survival have been published. OBJECTIVES: (i) To describe 1-year drug survival for adalimumab, etanercept and ustekinumab in a daily practice psoriasis cohort, and (ii) to introduce the concept of 'happy' drug survival, defined as Dermatology Life Quality Index (DLQI) ≤ 5 combined with being 'on drug' at a specific time point. METHODS: Data were extracted from a prospective registry. Drug survival was analysed using Kaplan-Meier estimates. 'Happy' drug survival was calculated, with data split into 'happy' (DLQI ≤ 5) vs. 'unhappy' (DLQI > 5) at baseline and months 3, 6, 9 and 12. RESULTS: 249 treatment episodes were included (101 adalimumab, 82 etanercept, 66 ustekinumab). The 1-year drug survival rates for ustekinumab, adalimumab and etanercept were 85%, 74% and 68%, respectively. Ustekinumab showed a better confounder-corrected drug survival vs. etanercept [hazard ratio (HR) 3·8, P = 0·02] and a trend towards better survival vs. adalimumab (HR 2·3, P = 0·1). At baseline, the majority (n = 115, 73%) was considered 'unhappy' and a minority 'happy' (n = 42, 27%) (ratio 'happy':'unhappy' was 1 : 2.7). The percentage of treatment episodes with 'happy' on-drug patients increased to 79% after 1 year. CONCLUSIONS: Ustekinumab showed a better overall drug survival than etanercept, and a trend towards a better overall drug survival than adalimumab. After 1 year, patients reported to be 'happy' in 79% of episodes and 'unhappy' in 21%. We introduced the new concept of 'happy' drug survival because the proportion of on-drug patients with good quality of life is an important indicator for treatment success.

Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dutch Society of Dermatology and Venereology.

This document provides a summary of the Dutch S3-guidelines on the treatment of psoriasis. These guidelines were finalized in December 2011 and contain unique chapters on the treatment of psoriasis of the face and flexures, childhood psoriasis as well as the patient's perspective on treatment. They also cover the topical treatment of psoriasis, photo(chemo)therapy, conventional systemic therapy and biological therapy.

Increased incidence of squamous cell carcinoma of the skin after long-term treatment with azathioprine in patients with auto-immune inflammatory rheumatic diseases.

BACKGROUND: Auto-immune inflammatory rheumatic diseases (AIRD) are often successfully treated with the immunosuppressant azathioprine for years. Treatment with azathioprine has been proven to increase the risk of non-melanoma skin cancer (NMSC) in transplant patients and possibly in patients with inflammatory bowel disease as well. Little is known about the risk of NMSC in AIRD patients treated with azathioprine. OBJECTIVES: The aim of this study is to determine the incidence of NMSC in patients with AIRD treated with azathioprine for at least 1 year, as compared with the general Dutch population. METHODS: Data were extracted from a historical cohort of patients with AIRD in a tertiary care centre. We compared the incidence to an age-matched control population and analysed risk factors for NMSC with univariate logistic regression. RESULTS: Fifty-nine patients were analysed. No patients were diagnosed with basal cell carcinoma and four patients with a single squamous cell carcinoma (SCC). Patients with SCC had a higher cumulative dose of azathioprine (≥ 500 g: OR 30.0 [95% CI 2.6-345.1]) and longer treatment duration (≥ 11 years: OR 13.5 [95% CI 1.3-143.6]). The risk of SCC compared with the general Dutch population was increased (standardized incidence ratio of 16.0 [95% CI 0.3-31.7]). CONCLUSIONS: In this cohort of patients with AIRD treated with azathioprine for at least 1 year, the risk of SCC was increased, as compared with the general population. An individual cumulative dose of at least 500 g azathioprine and a treatment duration of at least 11 years were quantified as risk factors.

Determinants of drug survival for etanercept in a long-term daily practice cohort of patients with psoriasis.

BACKGROUND: Long-term data of etanercept drug survival in patients with psoriasis in daily practice are scarce. OBJECTIVES: The primary objective was to describe drug survival for etanercept in a long-term daily practice cohort of patients with psoriasis. The secondary objective was to identify determinants of drug survival for etanercept in general and separately for discontinuation due to adverse events or ineffectiveness of therapy. METHODS: Data were extracted from a prospective daily practice cohort of patients treated with biologics for psoriasis. Drug survival was analysed by Kaplan-Meier survival curves and split for two reasons for discontinuation: adverse events and ineffectiveness. Determinants of drug survival were analysed using univariate Cox regression analysis and multivariate Cox regression analysis with backward selection. RESULTS: We included 193 patients (512 patient-years treated) with a maximum treatment duration of 7·5 years. The overall drug survival rates were 77%, 41% and 30% after 1, 4 and 7·5 years, respectively. The mean survival duration was 3·8 years (95% confidence interval 3·4-4·3). Reasons for discontinuation were ineffectiveness (33·7%), adverse events (11·9%), both ineffectiveness and adverse events (4·7%) or other reasons (e.g. pregnancy planned) (5·7%). Determinants related to longer general drug survival were male sex [hazard ratio (HR) 0·55], prior anti-tumour necrosis factor (TNF)-α use (HR 0·57) and lower etanercept dose (HR 0·65). Younger age (HR 0·83), lower body mass index (HR 0·63) and lower etanercept dose (HR 0·71) were related to a decreased risk of discontinuation due to side-effects. A lower mean weekly dose of etanercept (HR 0·63) was related to a decreased risk of discontinuation due to ineffectiveness of therapy. CONCLUSIONS: We present the longest analysis of drug survival for etanercept in psoriasis to date. Determinants of longer overall etanercept drug survival were male sex, prior anti-TNF therapy and lower etanercept dose. The determinants of longer drug survival depended on the reason for discontinuation of etanercept.

Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation?

BACKGROUND: Non-infective cutaneous granulomas with unknown pathogenesis occur in various primary immunodeficiencies (PIDs) including ataxia telangiectasia (A-T). OBJECTIVE: To find a common immunological denominator in these cutaneous granulomas. METHODS: The dermatological and immunological features of 4 patients with A-T and cutaneous granulomas were described. The literature on skin granulomas in A-T and in other PIDs is reviewed. RESULTS: All 4 A-T patients had progressive granulomas on their limbs and showed decreased IgG and IgA concentrations with normal IgM levels. They had a marked decrease in B cells and naïve T cells coinciding with the appearance of the cutaneous granulomas. Similar B- and T-cell abnormalities were described in patients with other PIDs with skin granulomas. CONCLUSIONS: We hypothesize that the pathogenesis of these skin granulomas is related to immune dysregulation of macrophages due to the absence of naïve T cells with an appropriate T-cell receptor repertoire and the unopposed activity of γδ T cells and/or natural killer cells.

Dithranol therapy in childhood psoriasis: unjustifiably on the verge of falling into oblivion.

BACKGROUND: In childhood psoriasis, physicians aim for an effective and safe treatment such as with dithranol. This study presents the largest study of dithranol-treated patients described in the literature. OBJECTIVE: The aim of the study was to determine the position of dithranol in the treatment strategy for psoriasis. METHODS: All juvenile patients receiving dithranol treatment at our center were evaluated retrospectively. RESULTS: Sixty patients (with 82 treatment episodes in total) were included. The mean age at the start of dithranol treatment was 11.1 years (range: 3.7-17.9 years). The result of the treatment was: excellent (3.7%), good (69.5%), moderate (8.5%), reasonable (13.4%) or disappointing (4.9%). Mild irritation was seen in 39%, and severe irritation in 63% of the patients. CONCLUSIONS: Dithranol can be regarded as an efficacious and safe topical therapy for the treatment of childhood psoriasis. It is a valuable alternative topical treatment which should not be disregarded in the treatment regimen for childhood psoriasis and should be commenced before ultraviolet or systemic treatments are initiated.

Palifermin-induced flexural hyperpigmentation: a clinical and histological study of five cases.

Palifermin is a human keratinocyte growth factor that is efficacious in reducing duration and severity of oral mucositis during autologous haematopoietic stem-cell transplantation for haematological cancer as well as chemotherapy for colorectal cancers. We report the clinical and histological characteristics of a series of five patients who developed flexural hyperpigmentation after treatment with palifermin. All patients showed ill-defined symmetrical hyperpigmented papillomatous plaques with slight erythema in the skin folds, especially affecting axillary and inguinal areas. The most striking histological finding was the thickened granular layer in all patients. We demonstrate that filaggrin, an essential component in the terminal differentiation of the epidermis, was upregulated in these cases. Palifermin-induced flexural hyperpigmentation is a newly defined clinical and histological entity. The possible aetiology is discussed.

Distribution of dipeptidyl-peptidase IV on keratinocytes in the margin zone of a psoriatic lesion: a comparison with hyperproliferation and aberrant differentiation markers.

The inflammation process in psoriatic skin is characterized by influx of leukocytes, hyperproliferation and aberrant differentiation of keratinocytes regulated via cytokines. Dipeptidyl-peptidase IV (DPPIV) is known to be upregulated on keratinocytes in the psoriatic lesion. The objective was to gain insight into dynamics of DPPIV expression and enzyme activity together with keratinocyte proliferation and differentiation markers during development of a psoriatic lesion, in order to investigate coherence in mechanisms behind the upregulation of DPPIV in psoriatic skin. The expression of DPPIV, Ki-67 antigen and keratin-16 (K16) was studied in the dynamic margin zone of the psoriatic lesion, examining skin sections of the clinically uninvolved skin, the early lesion and the chronic lesion of psoriatic patients compared to healthy volunteers using immunohistochemical and enzymehistochemical staining methods. DPPIV-expression and enzyme activity, Ki-67 antigen and K16 are significantly upregulated in the centre and inner margin of the lesion compared to clinically uninvolved skin and the healthy volunteers skin. Mutually between the centre and inner margin, this upregulation did not differ significantly. The clinical symptomless skin proved to have significantly elevated DPPIV enzyme activity compared to the skin of healthy volunteers. We demonstrate that DPPIV is expressed and enzymatically active well before the development of an overt psoriatic lesion. The abnormal DPPIV distribution in psoriatic skin does not coincide with known markers of aberrant growth and differentiation of keratinocytes, which makes DPPIV (expression and enzyme activity) a marker standing on its own.

Relevance of compartmentalization of T-cell subsets for clinical improvement in psoriasis: effect of immune-targeted antipsoriatic therapies.

BACKGROUND: Therapies targeting the T cell-mediated pathology of psoriasis have been found to achieve remarkable clinical improvement and have confirmed the crucial role of the immune system either in peripheral blood (PB) or in skin. No analyses of T-cell counts in both compartments have been conducted in order to confirm or refute the hypothesized shifts between them. OBJECTIVES: To gain more insight in the dynamics of compartmentalization of T cells between PB and lesional skin of patients with psoriasis, in response to immune-targeted antipsoriatic therapies. METHODS: Eighteen patients with psoriasis received either efalizumab (n = 9) or etanercept (n = 9) for 12 weeks. Biopsies were taken for immunohistochemical analysis of T-cell subsets and simultaneously T-cell subsets were isolated from PB specimens by flow cytometry. RESULTS: The Psoriasis Area and Severity Index declined significantly after 12 weeks of etanercept, but not for efalizumab. After treatment with efalizumab, a significantly decreased number of all T-cell subsets was found in the dermis. In the epidermis, CD4+, CD8+, CD25+, CD45RO+ and CD161+ T-cell subsets were significantly decreased. With respect to etanercept, few significant changes in T-cell subsets were found. The percentage of lymphocytes in PB was significantly elevated after efalizumab treatment regardless of responder status. CONCLUSIONS: Treatment with efalizumab establishes successful recompartmentalization of T-cell subsets with modest clinical efficacy after 12 weeks, whereas in etanercept-treated patients, a significant clinical response is no guarantee for significant changes in T-cell subsets in the different compartments. Reductions in T-cell subsets cannot be used as predictive markers for the clinical response to therapy. Interference with the studied T-cell populations in its own right seems not to be responsible for the clinical efficacy of efalizumab and etanercept.

CD26/dipeptidyl-peptidase IV in psoriatic skin: upregulation and topographical changes.

BACKGROUND: Psoriasis is known to affect 2-3% of the population and can be considered an organ-specific autoimmune disease. CD26/dipeptidyl-peptidase IV (DPP-IV) is a membrane-bound protease with diverse properties. In theory, the expression of CD26/DPP-IV has common grounds with three principal key players of the psoriatic pathogenesis: keratinocytes, T cells and cytokines. OBJECTIVES: To assess CD26/DPP-IV expression in psoriasis in order to expand on the search for complementary biomarkers related to inflammation and proliferation in psoriasis. METHODS: The pattern of expression of CD26/DPP-IV was investigated on the mRNA-, protein- and enzyme-functionality level using immunohistochemical, immunofluorescent and enzyme activity labelling techniques. RESULTS: An 11-fold significant increase of CD26/DPP-IV on the mRNA level was demonstrated in psoriatic epidermal sheets compared with normal skin. Immunohistochemistry on psoriatic sections showed a distinct patchy honeycomb-like CD26/DPP-IV staining in the suprapapillary layers. Moreover, a clearly distinguishable column-like staining pattern throughout the suprabasal compartment along the rete ridges was seen, whereas in normal skin these patterns were absent. Strikingly, CD26/DPP-IV enzyme activity correlated with this immunohistochemical reactivity pattern for the CD26/DPP-IV protein. The T-cell bound expression of CD26/DPP-IV in psoriatic skin was explicitly present, albeit in small quantities. CONCLUSIONS: Our data provide clear evidence for a versatile upregulation of CD26/DPP-IV expression in psoriatic (epi)dermis. Although the exact functional contribution remains speculative, the topographical distribution of this complex multifunctional protein suggests a suitable role as a complementary biomarker in psoriasis.

Efficacy of the pulsed dye laser in the treatment of localized recalcitrant plaque psoriasis: a comparative study.

BACKGROUND: Localized chronic plaque psoriasis, resistant to local therapy, may be very hard to treat. The treatment of these lesions with a pulsed dye laser (PDL) has been described before, but a comparative study between the PDL and a potent topical treatment has never been performed. OBJECTIVES: To compare the efficacy of the PDL in the treatment of localized, recalcitrant plaque psoriasis with a potent topical therapy, using calcipotriol/betamethasone dipropionate (Dovobet) as an active comparator. METHODS: Eight patients with psoriasis were treated with both PDL (585 nm) and calcipotriol/betamethasone dipropionate in an open, intrapatient, left-right comparison. A plaque severity score (sum score) and photographs were used to document the course of therapy. Patients reported pain on a visual analogue scale. RESULTS: Both treatments were well tolerated, although one patient left the study due to post-PDL treatment pain. A significant difference in the sum score 12 weeks after treatment was seen in favour of the PDL (62% vs. 19% reduction; P<0.05). Scores for erythema declined significantly at week 12 in both the PDL and the calcipotriol/betamethasone dipropionate group (P<0.001). Induration and desquamation scores were significantly reduced at week 12 in the PDL group, without a statistically significant reduction in calcipotriol/betamethasone-treated lesions. The pain scores declined with progressive PDL treatments, although not statistically significantly. CONCLUSIONS: PDL treatment might be considered for the treatment of localized, recalcitrant plaque psoriasis, when other topical therapies have failed.

The role of lesional T cells in recalcitrant psoriasis during infliximab therapy.

With infliximab therapy (anti-TNF-alpha) for plaque psoriasis, over 80% of patients reach > or = 75% PASI improvement in 10 weeks of treatment. We describe a patient with severe recalcitrant psoriasis who was treated with infliximab 5 mg/kg for 22 weeks. Rather than the expected improvement, this patient experienced an initial exacerbation, followed by the lack of efficacy over the entire 22-week period of treatment. Before, during and after treatment we performed immunohistochemical analyses on lesional biopsies, with respect to T cells, NK-T cells, epidermal growth and differentiation. We found a discrepancy between the clinical aggravation and marked reductions of lesional T cell subsets. The most prominent decrease was for CD4+ T cells (72-74%), which suggests that a reduction of T cells in the psoriatic plaque might not be a guarantee for positive clinical outcomes. Remarkably, the number of epidermal CD94+ NK-T cells correlated fairly well with the lack of clinical efficacy, supposing a pathogenic role for these cells in psoriasis. Further studies are needed to clarify the ambiguous role of conventional pathogenic T cells in plaque psoriasis.