Sporadic pemphigus foliaceus and class II human leucocyte antigen allele associations in the white British and Indo-Asian populations in the UK.

BACKGROUND: Pemphigus foliaceus (PF) has both genetic and environmental susceptibility factors. Current data on human leucocyte antigen (HLA) in patients with sporadic PF are limited. AIM: To better define the distribution of HLA alleles in patients with PF in the UK. METHODS: We recruited 36 patients [26 of white British (WB) descent, 10 of Indo-Asian (IA) descent] with PF who were living in the UK and 159 ethnically matched normal controls, and analysed their class II HLA DRB1 and DQB1 allele distribution. RESULTS: There was an increased frequency of DRB1*1404 in association with DQB1*0503 in IA patients with PF. The DRB1*04 allele group as a whole had an increased frequency (P < 0.001) in the WB patient group compared with controls. The alleles contributing to this significance were DRB1*0401 (P = 0.03) and DRB1*0404 (P < 0.01). CONCLUSION: This is the largest HLA association study in sporadic PF from the UK to date. There appears to be a difference in PF susceptibility alleles between WB and IA patients, highlighting the importance of racial variation in genetic susceptibility to disease development.

Cortisol reactivity and weight gain among adolescents who vary in prenatal drug exposure.

OBJECTIVE: Low inhibitory control is linked with weight gain among youth. Inhibitory problems are associated with disruption to the hypothalamic-pituitary-adrenal axis cortisol response. Increased cortisol predicts appetite and weight gain (though may be gender specific). This study hypothesized that cortisol reactivity explains the association between inhibition and weight gain while considering the moderating factors of early stressors to the hypothalamic-pituitary-adrenal axis (e.g. prenatal-drug exposure) and gender. METHODS: Adolescents with prenatal-drug exposure (n = 76) and non-exposed comparison adolescents (NE; n = 61) completed the Conner's Continuous Performance Test and provided salivary cortisol samples. BMI z-score were measured at the initial and 12-month follow-up evaluations. A bootstrapped moderated mediation analysis was conducted to test for conditional indirect effects of cortisol reactivity. RESULTS: Lower inhibition was associated with increased cortisol reactivity among youth who were NE, and increased cortisol reactivity was associated with weight gain among girls. Cortisol reactivity mediated the relation between inhibition and BMI z-score change for the girls in the group who was NE. CONCLUSION: Increased cortisol reactivity may play a mechanistic role in predicting weight gain among non-prenatally drug-exposed girls. Cortisol reactivity may be a biomarker for targeted interventions to improve biological regulation and ultimately health risk among girls.

The home environment and toddler physical activity: an ecological momentary assessment study.

BACKGROUND: Physical activity (PA) promotion/obesity prevention in toddlerhood should include home environments. OBJECTIVE: The aim of the study was to determine social/physical home environment factors associated with toddler PA using ecological momentary assessment (EMA, real-time data collection). METHODS: Low-income mother-toddler dyads were recruited and given a handheld EMA device (53 random beeps followed by social/physical environment survey over 8 d). Simultaneously, PA was assessed via accelerometry (data extracted 15 min before/after response, average activity counts per minute). Linear mixed-effects models were used, adjusting for toddler age, urban/suburban residence and time of day; covariate moderating effects were examined; within-subjects and between-subjects findings were reported. PA was hypothesized to be greater when toddlers are outside (vs. inside), children are nearby (vs. alone), toddlers are interacting with their mothers (vs. not) and TV is off (vs. on). RESULTS: The final count was 2454 EMA/PA responses for 160 toddlers (mean age 20 months, range 12-31; 55% male, 66% Black and 54% urban). Associations with PA include (within subjects) the following: outside location (212 additional counts min-1 ), children nearby (153 additional counts min-1 ) and interacting with mother (321 additional counts min-1 ), compared with alternatives. Age was moderated by outside location/PA association (within subjects), with 90 additional counts min-1 per 3-month age group outside vs. inside. No between-subjects or television/PA associations were found. CONCLUSIONS: Home environment factors were associated with PA, including outside location, children nearby and mother interaction. EMA is a novel method, allowing identification of contextual factors associated with behaviours in natural environments.

Maternal depressive symptoms and early childhood cognitive development: a meta-analysis.

BACKGROUND: Previous findings have been mixed regarding the relationship between maternal depressive symptoms and child cognitive development. The objective of this study was to systematically review relevant literature and to perform a meta-analysis. METHOD: Three electronic databases (PubMed, EMBASE, PsycINFO) were searched. Initial screening was conducted independently by two reviewers. Studies selected for detailed review were read in full and included based on a set of criteria. Data from selected studies were abstracted onto a standardized form. Meta-analysis using the inverse variance approach and random-effects models was conducted. RESULTS: The univariate analysis of 14 studies revealed that maternal depressive symptoms are related to lower cognitive scores among children aged ⩽56 months (Cohen's d = -0.25, 95% CI -0.39 to -0.12). The synthesis of studies controlling for confounding variables showed that the mean cognitive score for children 6-8 weeks post-partum whose mothers had high depressive symptoms during the first few weeks postpartum was approximately 4.2 units lower on the Mental Developmental Index (MDI) of the Bayley Scales of Infant and Toddler Development (BSID) compared with children with non-symptomatic mothers (B̂ = -4.17, 95% CI -8.01 to -0.32). CONCLUSIONS: The results indicated that maternal depressive symptoms are related to lower cognitive scores in early infancy, after adjusting for confounding factors. An integrated approach for supporting child cognitive development may include program efforts that promote maternal mental health in addition to family economic wellbeing, responsive caregiving, and child nutrition.

Prognostic factors in pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND: Pemphigus typically has a chronic course, although there is great variability in disease duration (DD) and time taken to disease remission (DR) between individuals with the disease. The reasons for this are unclear. OBJECTIVES: To explore the prognostic influence of epidemiological, clinical, immunological and genetic factors on disease course and remission in pemphigus vulgaris (PV) and pemphigus foliaceus (PF). METHODS: This was a retrospective study of patients with PV and PF, recruited from a single UK centre. Direct and indirect immunofluorescence and enzyme-linked immunosorbent assay studies for antidesmoglein (Dsg) antibodies were used to assess immunological factors. Polymerase chain reaction with sequence specific primers (PCR-SSP) was used to assess the Class II human leukocyte antigen status of patients. Prognostic endpoints investigated were time to initial first DR and total DD. RESULTS: Ninety-five patients were recruited (79 PV and 16 PF). Patients of Indo-Asian origin were significantly associated with longer DD than White-British patients (P = 0.029). In addition, younger age at onset was associated with a worse prognosis in terms of DD: the mean age at presentation of patients with DD of < 5 years was 49 years (SEM = 3.4) compared with 40 years (SEM = 1.9) in those with DD > 5 years (P = 0.039). A higher initial intercellular antibody titre on normal human skin substrate was associated with a greater time to initial DR (P = 0.007) and high anti-Dsg 3 levels at baseline were associated with a longer total DD (P = 0.03). CONCLUSIONS: Ethnic group, age at presentation, initial intercellular antibody titre and initial Dsg 3 antibody levels all had a significant impact on prognosis of pemphigus.

Pulsed intravenous cyclophosphamide and methylprednisolone therapy in refractory pemphigus.

BACKGROUND: Pemphigus is a rare autoimmune blistering disorder. The mainstay of current treatment is high-dose oral corticosteroid therapy in combination with a steroid-sparing agent. Adjuvant therapy is important for disease control and to reduce the iatrogenic effects of oral prednisolone. Pulsed therapy with intravenous methylprednisolone and cyclophosphamide (PPC) has been shown to be an effective treatment but there are currently few data on its use in patients who have failed to respond to conventional immunosuppression. OBJECTIVES: To report the clinical and immunological responses of 21 patients with pemphigus refractory to prednisolone and azathioprine or mycophenolate mofetil treated in our department with a standard protocol of monthly PPC. METHODS: Patients with pemphigus were identified who had undergone PPC therapy during the period between 1997 and 2006. Initial clinical severity and response to treatment was assessed. In addition, change in intercellular antibody titres and desmoglein 1 and 3 antibodies to PPC therapy was also recorded. RESULTS: Of the 21 patients treated, seven had an excellent response, two a good response, five a moderate response, six a minimal response and one patient had no clinical response. Four patients achieved complete clinical remission and the number of pulses for these patients varied between 11 and 22. We observed significant reductions in indirect immunofluorescence titres for normal human skin substrate (P = 0.0078) and antidesmoglein 1 and 3 autoantibody levels (P = 0.007 and P = 0.0085, respectively) from pre-PPC therapy to 1 year after the last pulse. All patients were able to reduce their prednisolone dose from a pre-pulsing median dose of 40-10 mg at the last pulse with a median dose reduction of 66% (P < 0.001). The most common adverse effect was transient lymphopenia (12 patients); nonlife-threatening sepsis (seven patients) and premature ovarian failure (two patients) also occurred. CONCLUSIONS: PPC can be an effective treatment for refractory pemphigus but its adverse effects should be considered prior to therapy and closely monitored in patients on treatment.

A scoring system for mucosal disease severity with special reference to oral lichen planus.

BACKGROUND: To date, there is only weak evidence for the superiority of any interventions over placebo for the palliation of symptomatic oral lichen planus (LP). Further research involving large placebo-controlled, randomized clinical trials is needed. These will require carefully selected and standardized outcome measures. OBJECTIVES: To formulate a scoring system for intraoral LP. METHODS: One hundred and fifty-six patients with biopsy-confirmed LP were scored at the first and subsequent visits according to (i) extent of site involvement, (ii) disease activity at each site and (iii) an overall pain score as reported by the patient. Overall differences between clinical variants of LP were analysed using the Kruskal-Wallis test and pairwise differences by the Mann-Whitney U-test. Clinical sensitivity (Wilcoxon signed-rank test) was assessed by scoring patients before and after treatment (n = 23). RESULTS: Reticular LP (n = 48) was the commonest single type of clinical presentation, followed by ulcerative (n = 30), atrophic (n = 22), desquamative (n = 18) and plaque (n = 1). The median severity and activity scores were 13/6 (reticular), 39/20 (ulcerative), 20/9 (atrophic) and 23/11 (desquamative). Two or more clinical variants were seen in 37 cases. Statistical significance was observed for differences between clinical variants (P < 0.0001) and variation in scores (P < 0.01) when ulcerative LP was compared with all other types. Clinical sensitivity was statistically significant (P < 0.01), while reproducibility was high and allowed the response to therapy to be easily assessed. CONCLUSIONS: It is suggested that this scoring system is easy to use, reproducible and sensitive enough to detect clinical responses to therapy.

A case of cutaneous extravascular necrotizing granuloma without systemic manifestations.

Cutaneous extravascular necrotizing granuloma, an unusual palisading dermal granuloma, was first described by Churg and Strauss in 1951 in association with the syndrome of allergic granulomatosis (Churg-Strauss syndrome), for which it was though to be pathognomonic. It has subsequently been described in association with a number of autoimmune and immunoreactive diseases, and is regarded as a cutaneous marker of systemic pathology. To our knowledge, only one patient has been reported with clinical features confined to the skin. We report a 46-year-old woman with recurrent cutaneous lesions over a 10-year period and the classic histopathological pattern, but no underlying systemic disease.

Paraneoplastic pemphigus associated with CD20-positive follicular non-Hodgkin's lymphoma treated with rituximab: a third case resistant to rituximab therapy.

Paraneoplastic pemphigus is an IgG-mediated disease characterized clinically by a polymorphous blistering eruption with severe mucosal involvement associated with an underlying or occult malignancy. It is associated with high mortality, and response to treatment is generally poor. Potent immunosuppression is often necessary to control progression of the disease. Three case reports have documented successful treatment of paraneoplastic pemphigus with rituximab, an anti-CD20 monoclonal antibody. However, two previous reports have noted that rituximab was unsuccessful in halting progression of PNP. We report a third case of paraneoplastic pemphigus associated with follicular non-Hodgkin's lymphoma in which rituximab was not effective. Whether rituximab is an effective and novel treatment for paraneoplastic pemphigus remains undecided.

Polymorphic eruption of pregnancy: clinicopathology and potential trigger factors in 181 patients.

BACKGROUND: Polymorphic eruption of pregnancy (PEP; synonym: pruritic urticarial papules and plaques of pregnancy) is the most common specific dermatosis of pregnancy. However, its clinical characterization is controversial and its pathogenesis uncertain. OBJECTIVES: To evaluate clinical characteristics of and potential trigger factors for PEP in a large mixed ethnic population. METHODS: A retrospective analysis of epidemiological, clinical, immunopathological and obstetric findings in 181 patients with PEP seen at two university-based dermatological hospitals in Graz, Austria, and London, U.K. RESULTS: PEP mainly affected white (88%) primigravidae (70%) in late pregnancy (83%; mean +/- SD onset 34 +/- 5 weeks) or the immediate postpartum period (15%). The most commonly involved sites were the abdomen and proximal thighs (97%). Involvement of the whole skin, including the face, palms and soles, was only rarely observed. While pruritic urticarial papules and plaques were the main morphological features at disease onset (98%), more than one-half of the patients (51%) later developed polymorphous features including erythema, vesicles, and targetoid and eczematous lesions. Topical treatment with corticosteroids and emollients was sufficient to control symptoms in the majority of patients, and skin lesions resolved after a mean +/- SD of 4 +/- 3 weeks. Multiple gestation pregnancies were observed in 13% of cases, excessive maternal weight gain in 78%. CONCLUSIONS: Our data confirm the benign, self-limiting nature of PEP and its favourable outcome for both the mother and the fetus. For the first time, we have documented a characteristic change in morphology with disease progression. The evidence of polymorphous clinical features in more than one-half of the patients favours the use of the term PEP. Multiple gestation pregnancies and excessive maternal weight gain, but not fetal weight and sex, were found to be significantly associated with PEP.

Evidence of an association between desmoglein 3 haplotypes and pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV, OMIM 169610) is a severe blistering disorder of the skin and mucous membranes, caused by the production of autoantibodies directed against the epithelial adhesive protein desmoglein 3. Although an association between PV and HLA class II alleles has been established, the genetic factors predisposing to the disease remain poorly understood, the rarity of PV hampering the recruitment of substantial patient cohorts. OBJECTIVES: To investigate DSG3 as a candidate PV susceptibility gene. METHODS: We examined five DSG3 single nucleotide polymorphisms (rs8085532, rs3911655, rs3848485, rs3794925 and rs1466379) in two case-control datasets respectively originating from the U.K. (62 PV patients, 154 controls) and northern India (28 patients, 98 controls). RESULTS: In the U.K. sample, we observed a significant association between PV and the DSG3*TCCTC haplotype (Fisher's exact test P = 0.002). A related haplotype (DSG3*TCCCC) was associated with PV in the Indian dataset (P = 0.002). We also found that all British and Indian patients bearing DSG3 risk haplotypes carried at least one copy of a PV-associated HLA allele. CONCLUSIONS: These results suggest that genetic variation of DSG3 may be an additive risk factor predisposing to PV and warrant further investigations of this gene.