Agneta Gånemo

Congenital ichthyosis: an overview of current and emerging therapies.

Congenital ichthyosis is a collective name for a group of monogenetic disorders of cornification, sometimes associated with systemic symptoms. There may be an abnormal quality or quantity of scale produced, abnormal thickness of stratum corneum or abnormal keratinocyte kinetics, often associated with skin inflammation. Pruritus, skin fragility, ectropion and anhidrosis are sometimes associated with the rare types of ichthyosis. Three important mechanisms are involved in the action of topical agents used in the treatment of ichthyosis: hydration, lubrication and keratolysis. The latter effect can also be achieved with systemic retinoids. For ichthyosis with an increased tendency towards skin infections, antimicrobials are another group of widely used agents. Considering that patients with ichthyosis are potential mega-users of topical therapy, with an estimated lifetime consumption of approximately one tonne cream per capita, surprisingly few controlled trials of the various treatments have been performed. Moreover, nearly all therapeutic principles were established long before the recent increase in knowledge about the aetiology and pathophysiology of ichthyosis. This calls for new ideas and intensified efforts to develop future ichthyosis therapies.

Congenital ichthyosis: mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis

Background: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood. Methods: To investigate genotype–phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI. Results: Mutation screening of ichthyin revealed missense or splice-site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin. Discussion: Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI.

Quality of Life and Clinical Features in Swedish Children with Psoriasis.

Abstract:  Psoriasis is a common, chronic disease and in one‐third of the patients it begins during the first 2 decades of life. The burdens of psoriasis are many, and some can be assessed with quality of life questionnaires. The aim was to investigate the impact of childhood psoriasis on quality of life in children and their parents and to correlate certain clinical findings with quality of life. Forty‐five Swedish children (4–16 years, 28 girls) with psoriasis, and their parents, were investigated with the validated questionnaires Children’s Dermatology Life Quality Index (5–16 years, n = 42), The Infant’s Dermatitis Quality of Life Index (4 years, n = 3), and Dermatitis Family Impact (n = 45), the two latter with the word eczema replaced by psoriasis. Clinical examination was performed, and psoriasis severity was scored with Psoriasis Area and Severity Index. Chronic plaque psoriasis was the most common clinical type (87%). Four of the children had joint complaints. Ninety‐three percent had pruritus the preceding 3 days. Ninety‐three percent were receiving treatment. Median Psoriasis Area and Severity Index score was 3.3 (range 0.5–12.3). Median score for the Infant’s Dermatitis Quality of Life Index was 4.0 (range 2–12), for Children’s Dermatology Life Quality Index 4.0 (0–24), and for Dermatitis Family Impact questionnaire 4.0 (0–25). No significant gender difference existed. The Children’s Dermatology Life Quality Index scores were higher for younger (5–8 yrs) than older (9–16 yrs) children and higher for those with joint complaints. The Dermatitis family impact scores correlated significantly with Children’s Dermatology Life Quality Index and Psoriasis Area and Severity Index scores, but the Children’s Dermatology Life Quality Index did not correlate with Psoriasis Area and Severity Index. The Visual Analog Scale and quality of life scores were significantly correlated. Psoriasis in children affects quality of life in the subjects and their parents. Joint complaints and pruritus significantly impair quality of life.

A systematic review of tacrolimus ointment compared with corticosteroids in the treatment of atopic dermatitis

Abstract Objective: A systematic review and meta-analysis was conducted to determine the efficacy and tolerability of tacrolimus ointment for the treatment of atopic dermatitis (AD) compared with topical corticosteroids. Methods: Electronic searches were performed in Medline, Embase and the Cochrane Library, as well as relevant conference proceedings. Two researchers independently selected trials investigating the efficacy and/or safety of tacrolimus ointment in the treatment of AD. No language restrictions were applied. Relevant outcome data from included trials were extracted by two independent reviewers. Direct meta-analysis to calculate relative risks (RR) (95% confidence intervals (CIs)) was conducted on dichotomous efficacy/safety outcomes of interest. Results: Seventeen trials comparing tacrolimus ointment with topical corticosteroids in both paediatric (n = 2328) and adult (n = 2849) patients were identified. No studies comparing tacrolimus ointment with class IV topical corticosteroids were identified. Tacrolimus 0.1% ointment was found to be of similar efficacy to class I/II and class III topical corticosteroids. In three individual trials (comparing tacrolimus 0.1% ointment to a topical corticosteroid), evaluation of the Physicians Global Evaluation of Clinical Response (PGECR) resulted in RRs of 0.95 (95% CI 0.78–1.16), 3.09 (95% CI 2.14–4.45) and 1.35 (95% CI 0.86–2.12), where values above one favour tacrolimus ointment. With the exception that tacrolimus ointment caused more skin burning than comparator treatments (tacrolimus 0.03% versus a class III topical corticosteroid, the RR was 3.00 (95% CI 1.21–7.43) in favour of the corticosteroid), no significant differences with regards to side-effects and withdrawals due to AEs were found. Quality of life data were reported in two studies. While one study reported greater improvements in tacrolimus-treated adult patients compared with topical steroids, the second reported greater improvements in paediatric patients treated with steroids compared with tacrolimus ointment. Conclusions: The current review and meta-analysis showed tacrolimus ointment to be of similar efficacy to corticosteroids. The interpretation of available data is limited by heterogeneity in outcome measures between trials. Further trials are needed to assess the impact of treatments on patient reported outcomes.

Sjögren-larsson syndrome: a study of clinical symptoms and dermatological treatment in 34 Swedish patients.

Sjögren-Larsson syndrome (SLS) is a recessively inherited disease with congenital ichthyosis, spastic diplegia or tetraplegia and mental retardation, caused by a deficiency of fatty aldehyde dehydrogenase. The aim of this study was to examine all 34 Swedish patients with SLS, emphasizing skin symptoms, dermatological treatment, and neurological symptoms (evaluated in some cases for more than 25 years by one and the same investigator). Structured interviews were conducted with the patients and their close relatives. All patients had generalized ichthyosis. The degree of scaling varied markedly inter-individually from moderate to severe, but there was no obvious change with age. Most patients had pruritus, suffered from hypohidrosis, and had palmo-plantar keratoderma. Nineteen patients (56%) were on oral acitretin and all patients were using some type of topical therapy. Motor disability with spasticity and muscular paresis was most pronounced in the legs and fairly slight in the arms. Twenty patients (59%) were dependent on a wheelchair for mobility. Poor blood circulation in the lower legs and oedematous feet were frequently found in adults. All patients had learning disability, which varied from slight to pronounced and was expressed in their speech disorders. Thirteen patients (38%) were being treated medically for epilepsy and all had photophobia. In conclusion, SLS is a chronic, severely disabling neurocutaneous disease in which optimal dermatological therapy is essential to relieve at least the patients ichthyosis problem.

Expression of retinoid-regulated genes in lamellar ichthyosis vs. healthy control epidermis: changes after oral treatment with liarozole.

Lamellar ichthyosis is a keratinization disorder caused by TGM1, Ichthyin and several other gene mutations. A new treatment option is liarozole, which blocks the cytochrome P450 (CYP26)-mediated catabolism of endogenous all-trans retinoic acid. This study focuses on the expression of retinoid-related genes in ichthyotic epidermis before and after treatment with oral liarozole. We first compared the mRNA expression of cellular retinoic acid binding protein II (CRABPII), keratin (KRT) 2 and 4, CYP26A1 and B1, and two markers of inflammation (interleukin-1alpha and tumours necrosis factor (TNF)-alpha) in shave biopsies from 11 genetically defined, untreated patients and 12 age- and sex-matched healthy controls, finding no overt differences between the groups, besides elevated CRABPII expression. We then studied the biomarkers before and after 4 weeks of treatment with liarozole (75 or 150 mg/day), which produced a better therapeutic response in patients with Ichthyin (n=3) than in those with TGM1 (n=6) mutations. A significant decrease in the mRNA expression of KRT2 and TNF-alpha, and trends toward increased expression of KRT4 and CYP26A1 were observed in liarozole-treated patients, consistent with an increased retinoid stimulation of epidermis. However, there were no dose-related responses and the results of the immunostaining did not always parallel the mRNA findings. The results suggest that liarozole exerts a therapeutic effect in lamellar ichthyosis by mildly affecting the expression of retinoid- regulated genes in epidermis.

Spectrum of autosomal recessive congenital ichthyosis in scandinavia : Clinical characteristics and novel and recurrent mutations in 132 patients

Autosomal recessive congenital ichthyosis (ARCI) represents a heterogeneous group of rare disorders of cornification with 3 major subtypes: harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A 4th subtype has also been proposed: pleomorphic ichthyosis (PI), characterized by marked skin changes at birth and subsequently mild symptoms. In nationwide screenings of suspected cases of ARCI in Denmark and Sweden, we identified 132 patients (age range 0.1-86 years) classified as HI (n = 7), LI (n = 70), CIE (n = 17) and PI (n = 38). At birth, a collodion membrane or similar severe hyperkeratosis was reported in almost all patients with HI and LI, and in nearly half of patients with CIE and PI. Persistent ectropion was more common in HI (85%) and LI (57%), than in CIE (35%) and PI (5%). Anhidrosis was a frequent problem in all 4 groups (58-100%). A scoring (0-4) of ichthyosis/ery-thema past infancy showed widely different mean values in the subgroups: HI (3.2/3.1), LI (2.4/0.6), CIE (1.8/1.6), PI (1.1/0.3). Novel or recurrent mutations were found in 113 patients: TGM1 (n = 56), NIPAL4 (n = 15), ALOX12B (n = 15), ABCA12 (n = 8), ALOXE3 (n = 9), SLC27A4 (n = 5), CYP4F22 (n = 3), PNPLA1 (n = 1) and ABHD5 (n = 1). In conclusion, by performing a deep phenotyping and gene screening, ARCI can be definitely diagnosed in 85% of cases in Scandinavia, with a prevalence of 1:100,000 and > 8 different aetiologies.

Oral Alitretinoin in Congenital Ichthyosis: A Pilot Study Shows Variable Effects and a Risk of Central Hypothyroidism

Congenital ichthyosis is a large group of hereditary skin disorders with different aetiologies, all of which are pre-sent at birth (1). The patients have dry, widespread scaling and thickened skin (2). At present there is no cure for ichthyosis and therapy is mostly symptomatic. Life-long treatment with emollients is essential, and some patients also use systemic therapy with retinoids, especially aci-tretin (3). The most serious adverse effect of retinoids is teratogenicity, which is a special concern for acitretin as it is excreted from the body slowly (3).Alitretinoin (9-cis retinoic acid) is a fairly new oral retinoid with more rapid clearance than acitretin. In contrast to acitretin and isotretinoin, alitretinoin binds to both types of nuclear retinoid receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). It is indicated for chronic hand eczema in most European countries and has been found to be well-tolerated (4). We report here our preliminary experiences from an uncontrolled study of alitretinoin in 4 patients with congenital ichthyosis. PATIENTS AND METHODS

Scoring of hand eczema : good agreement between patients and dermatological staff

Background  Assessment of hand eczema in a clinical study has been achieved using a scoring system which documents extent of eczema on different areas of the hand.

Usefulness of Rajka and Langeland Eczema Severity Score in Clinical Practice.

Simple, validated eczema severity scores are required for the evaluation of interventions. The Rajka & Langeland (R&L) scale is based on 3 domains (extent, course, and intensity); however, its validity is not yet confirmed. The aim of this study was to investigate the quality aspects of the R&L scale in clinical practice. In the first part of the study, experts and consumers judged the content validity of the scale. The second part of the study was performed with 87 children during a 4-month eczema school. Construct validity, internal consistency, sensitivity to change, time consumption and health-related quality of life variables were investigated. The content of the R&L scale was considered valid by 45 panellists. Inter- and intra-observer reliability was very good. Divergent construct validity was adequate, while convergent construct validity and internal consistency were inadequate. The R&L scale was able to define a significant improvement in eczema during the eczema school. The time required for completing the R&L assessment was significantly shorter than for objective Severity Scoring of Atopic Dermatitis (SCORAD). The R&L scale is a simple, fast, valid, reliable and sensitive tool for scoring of atopic dermatitis in everyday clinical practice.