Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life. OBJECTIVES AND METHODOLOGY: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice.

Cannabinoid receptor type 2 is upregulated in synovium following joint injury and mediates anti-inflammatory effects in synovial fibroblasts and macrophages.

OBJECTIVE: Joint injury-induced perturbations to the endocannabinoid system (ECS), a regulator of both inflammation and nociception, remain largely uncharacterized. We employed a mouse model of ACL rupture to assess alterations to nociception, inflammation, and the ECS while using in vitro models to determine whether CB2 agonism can mitigate inflammatory signaling in macrophages and fibroblast-like synoviocytes (FLS). DESIGN: Mice underwent noninvasive ACL rupture (ACLR) via tibial compression-based loading. Nociception was measured longitudinally using mechanical allodynia and knee hyperalgesia testing. Synovitis was assessed using histological scoring and histomorphometry. Gene and protein markers of inflammation were characterized in whole joints and synovium. Immunohistochemistry assessed injury-induced alterations to CB1+, CB2+, and F4/80+ cells in synovium. To assess whether CB2 agonism can inhibit pro-inflammatory macrophage polarization, murine bone marrow-derived macrophages (mBMDM) were stimulated with IL-1ß or conditioned medium from IL-1ß-treated FLS and treated with vehicle (DMSO), the CB2 agonist HU308, or cannabidiol (CBD). Macrophage polarization was assessed as the ratio of M1-associated (IL1b, MMP1b, and IL6) to M2-associated (IL10, IL4, and CD206) gene expression. Human FLS (hFLS) isolated from synovial tissue of OA patients were treated with vehicle (DMSO) or HU308 following TNF-α or IL-1ß stimulation to assess inhibition of catabolic/inflammatory gene expression. RESULTS: ACLR induces synovitis, progressively-worsening PTOA severity, and an immediate and sustained increase in both mechanical allodynia and knee hyperalgesia, which persist beyond the resolution of molecular inflammation. Enrichment of CB2, but not CB1, was observed in ACLR synovium at 3d, 14d, and 28d, and CB2 was found to be associated with F4/80 (+) cells, which are increased in number in ACLR synovium at all time points. The CB2 agonist HU308 strongly inhibited mBMDM M1-type polarization following stimulation with either IL-1ß or conditioned medium from IL-1ß-treated mFLS, which was characterized by reductions in Il1b, Mmp1b, and Il6 and increases in Cd206 gene expression. Cannabidiol similarly inhibited IL-1ß-induced mBMDM M1 polarization via a reduction in Il1b and an increase in Cd206 and Il4 gene expression. Lastly, in OA hFLS, HU308 treatment inhibited IL-1ß-induced CCL2, MMP1, MMP3, and IL6 expression and further inhibited TNF-α-induced CCL2, MMP1, and GMCSF expression, demonstrating human OA-relevant anti-inflammatory effects by targeting CB2. CONCLUSIONS: Joint injury perturbs the intra-articular ECS, characterized by an increase in synovial F4/80(+) cells, which express CB2, but not CB1. Targeting CB2 in murine macrophages and human FLS induced potent anti-inflammatory and anti-catabolic effects, which indicates that the CB2 receptor plays a key role in regulating inflammatory signaling in the two primary effector cells in the synovium. The intraarticular ECS is therefore a potential therapeutic target for blocking pathological inflammation in future disease-modifying PTOA treatments.

Knowledge and competency standards for specialized cognitive behavior therapy for pediatric obsessive-compulsive disorder.

Although exposure-based cognitive behavior therapy (CBT) and pharmacotherapy have demonstrated efficacy for obsessive-compulsive disorder (OCD), the lack of clinicians effectively trained in these treatments significantly limit effective intervention options for affected youth. This is very unfortunate since child onset is reported by 50% of adults with OCD. To ameliorate this serious global issue the 14 nation International Obsessive-Compulsive Disorders Accreditation Task Force (ATF) of The Canadian Institute for Obsessive Compulsive Disorders (CIOCD) has developed knowledge and competency standards recommended for specialized treatments for OCD through the lifespan. Currently available guidelines are considered by experts to be essential but insufficient because there are not enough clinicians with requisite knowledge and competencies to effectively treat OCD. This manuscript presents knowledge and competency standards recommended for specialized cognitive behavior therapy (CBT) for pediatric OCD, derived from comprehensive literature review and expert synthesis. In addition to standards covering the elements of individual CBT-based assessment and treatment, family and school interventions are addressed given the critical role these domains play in the psychosocial development of youths. The ATF standards presented in these phase two papers will be foundational to the upcoming development of certification (individuals) and accreditation (sites) for specialized treatments in OCD through the lifespan.

Response of spring wheat and potato to foliar application of Zn, Mn and EDTA fertilizers on 137Cs uptake.

The impact of foliar fertilization with zinc (ZnSO4) and manganese (MnSO4 on 137Cs uptake by spring wheat and potato was studied. The experiments were conducted during 3 years (2014-2016) in a137Cs-contaminated area, Zhytomyr region of Ukraine. The fertilization was carried out on podzolic loamy sand soil, poor in most of the microelements. Both crops were fertilized at four successive stages of growth. Foliar application of fertilizers caused higher yield of wheat grain/straw and potato tubers yield in 2014-2015 years but had no effect in 2016. Thus, the overall effect of fertilization between 2014 and 2016 was less pronounced and generally insignificant. Application of Zn, Mn and EDTA reduced 137Cs uptake by wheat grain and potato tubers, when fertilized at earlier stages of growth and development in years 2014 and 2015 by factor 1.5-2.0, while in 2016 the effect was generally statistically insignificant. It is suggested, that reduction of 137Cs uptake by spring wheat and potato, at least partly, was caused by an effect of radionuclide dilution due to the higher biomass of the plants. A foliar spray of EDTA at earlier stages of plant growth and development may be considered as a potential countermeasure aiming reducing 137Cs uptake from soil to plants, even if such effect appeared to be conditional.

Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV).

BACKGROUND: Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the United States. OBJECTIVES: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. RESULTS: The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations.

The Selective Mutism Questionnaire: Data from typically developing children and children with selective mutism.

The core symptom of the anxiety disorder selective mutism (SM) is absence of speech in specific situations, such as at school. The most commonly used standardized instruments to assess speaking behavior are the parent-rated Selective Mutism Questionnaire (SMQ) and the teacher-rated School Speech Questionnaire (SSQ), scored from 0 to 3, indicating that speaking behavior never, seldom, often, and always occur. They were developed to assess severity of mutism and potential effects of treatment. However, prospective data on speaking behavior in typically developing children (TDs) are missing in the literature. The main aim of this study was to present data from TDs over time with previously reported data from children treated for SM, as a comparison. Participants were 64 children aged 3-9 years, 32 TDs who were a matched control group to 32 children with SM. At baseline, the mean SMQ and SSQ scores were ⩾2.5 in TDs and 0.5 in children with SM. The TDs did not show significant changes over time, while significantly increased speech was found in children with SM after treatment. Thus, our findings support the use of the SMQ/SSQ to assess baseline SM severity and to evaluate potential treatment effects in future studies.

Improvement in anxiety and depression symptoms following cognitive behavior therapy for pediatric obsessive compulsive disorder.

Pediatric obsessive-compulsive disorder (OCD) co-occurs frequently with other mental health conditions, adding to the burden of disease and complexity of treatment. Cognitive behavioral therapy (CBT) is efficacious for both OCD and two of its most common comorbid conditions, anxiety and depression. Therefore, treating OCD may yield secondary benefits for anxiety and depressive symptomatology. This study examined whether anxiety and/or depression symptoms declined over the course of OCD treatment and, if so, whether improvements were secondary to reductions in OCD severity, impairment, and/or global treatment response. The sample consisted of 137 youths who received 12 sessions of manualized CBT and were assessed by independent evaluators. Mixed models analysis indicated that youth-reported anxiety and depression symptoms decreased in a linear fashion over the course of CBT, however these changes were not linked to specific improvements in OCD severity or impairment but to global ratings of treatment response. Results indicate that for youth with OCD, CBT may offer benefit for secondary anxiety and depression symptoms distinct from changes in primary symptoms. Understanding the mechanisms underlying carryover in CBT techniques is important for furthering transdiagnostic and/or treatment-sequencing strategies to address co-occurring anxiety and depression symptoms in pediatric OCD.

Hoarding Symptoms in Children and Adolescents With Obsessive-Compulsive Disorder: Clinical Features and Response to Cognitive-Behavioral Therapy.

OBJECTIVE: Although adult hoarding disorder is relatively common and often debilitating, few studies have examined the phenomenology of pediatric hoarding. We examined the clinical phenomenology and response to cognitive-behavioral therapy (CBT) treatment in youths with a diagnosis of obsessive-compulsive disorder (OCD) with and without hoarding symptoms. Age was tested as a moderator across analyses, given prior findings that the impact of hoarding symptoms may not become apparent until adolescence. METHOD: Youths (N = 215; aged 7-17 years) with OCD pursuing evaluation and/or treatment at a university-based specialty clinic participated in the current study. Presence of hoarding symptoms was assessed as part of a larger battery. Data from a subset of youths (n = 134) who received CBT were included in treatment response analyses. RESULTS: Youths with hoarding symptoms did not differ from those without hoarding symptoms with respect to overall OCD symptom severity and impairment. Youths with hoarding met criteria for more concurrent diagnoses, including greater rates of internalizing and both internalizing/externalizing, but not externalizing-only, disorders. Youths with and without hoarding symptoms did not significantly differ in rate of response to CBT. Age did not moderate any of these relationships, suggesting that the presence of hoarding symptoms was not associated with greater impairments across the clinical presentation of OCD or its response to treatment by age. CONCLUSION: We found no evidence that hoarding is associated with greater OCD severity or poorer treatment response in affected youth. Theoretical and clinical implications of these findings, including future directions for research on testing developmental models of hoarding across the lifespan, are discussed.

Comparing OCD-affected youth with and without religious symptoms: Clinical profiles and treatment response.

BACKGROUND: Childhood obsessive-compulsive disorder (OCD) is a heterogeneous psychiatric condition, with varied symptom presentations that have been differentially associated with clinical characteristics and treatment response. One OCD symptom cluster of particular interest is religious symptoms, including fears of offending religious figures/objects; patients affected by these symptoms have been characterized as having greater overall OCD severity and poorer treatment response. However, the extant literature primarily examines this symptom subtype within adults, leaving a gap in our understanding of this subtype in youth. METHOD: Consequently, this study examined whether presence of religious symptoms in OCD-affected children and adolescents (N = 215) was associated with greater clinical impairments across OCD symptoms and severity, insight, other psychiatric comorbidity, family variables, or worse treatment response. RESULTS: Results found that youth with religious OCD symptoms presented with higher OCD symptom severity and exhibited more symptoms in the aggressive, sexual, somatic, and checking symptom cluster, as well as the symmetry, ordering, counting, and repeating cluster. Religious OCD symptoms were also significantly associated with poorer insight and higher family expressiveness. No differences in treatment response were observed in youths with versus without religious OCD symptoms. CONCLUSION: Ultimately, youths with religious OCD symptoms only differed from their OCD-affected counterparts without religious symptoms on a minority of clinical variables; this suggests they may be more comparable to youths without religious OCD symptoms than would be expected based on the adult OCD literature and highlights the importance of examining these symptoms within a pediatric OCD sample.

Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study.

AIMS: To determine the role of total skin electron irradiation (TSEI) as a cause of second malignancies in mycosis fungoides patients. MATERIALS AND METHODS: Mycosis fungoides patients referred to TSEI were followed in a longitudinal study. Other diagnosed malignancies were obtained after cross-matching with the Israel National Cancer Registry database. RESULTS: Between 1974 and 2010, 197 patients were treated: 134 (68%) men, 63 (32%) women; mean age 58 ± 17years. Topical/systemic treatment was given to 134 (68%) patients. TSEI was given to 104 (68.9%) patients. Seven (4.6%) received sub-TSEI and 40 (26.5%) received focal electron irradiation fields. Forty-six (23%) patients did not receive radiotherapy. The second primaries rate was 6.7 times higher in male mycosis fungoides patients and 13.1 times higher in female mycosis fungoides patients than in the general Israeli population. Malignant melanoma developed in eight patients after radiotherapy, in one patient without irradiation. The skin-related cancer rate after irradiation versus no irradiation was higher (P = 0.018). Combination radiotherapy with psoralen + ultraviolet A and/or nitrogen mustard yielded 11 cases of skin cancer versus no cases without irradiation. CONCLUSIONS: Mycosis fungoides patients have a high incidence of sequential malignancies. TSEI is associated with higher 'skin-related cancer' rates. Close longitudinal follow-up of mycosis fungoides patients is obligatory.

The pharmacokinetics of cytarabine administered subcutaneously, combined with prednisone, in dogs with meningoencephalomyelitis of unknown etiology.

The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m2 as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5-2 mg kg-1 day-1 ). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling (NLME). Plasma drug concentrations ranged from 0.05 to 2.8 µg/ml. The population estimate (CV%) for elimination half-life and Tmax of cytarabine in dogs was 1.09 (21.93) hr and 0.55 (51.03) hr, respectively. The volume of distribution per fraction absorbed was 976.31 (10.85%) ml/kg. Mean plasma concentration of CA for all dogs was above 1.0 µg/ml at the 30-, 60-, 90-, and 120-min time points. In this study, the pharmacokinetics of CA in dogs with MUE after a single 50 mg/m2 SC injection in dogs was similar to what has been previously reported in healthy beagles; there was moderate variability in the population estimates in this clinical population of dogs.

Altered expression of regulatory molecules in the skin of psoriasis.

The presence of T regulatory cells (Tregs) is highly required in normal skin in order to maintain immune tolerance to commensal microbes and to prevent the development of immune-mediated inflammation. Psoriasis is a chronic inflammatory skin disease in which effector T cells, namely, Th17 and their relevant pro-inflammatory cytokines are increased in peripheral blood as well as in the inflamed skin. The status of Tregs in psoriatic skin is continuously studied. In this case, CD4 + CD25high T cells and other regulatory cytokines such as IL-35 are demonstrated to be significantly decreased. Aiming to better characterize Tregs in psoriatic skin and to establish the finding of their abnormal balance, we assessed the expression of semaphorin3A and neuropilin-1 (both reported as biomarkers of Tregs). Semaphorin3A and neuropilin-1 expressing Tregs were found to be significantly decreased in psoriatic skin when compared to normal skin. These findings were supported by demonstrating the downregulation of IL-10 expression in psoriatic skin. Our findings suggest that semaphoring3A may turn to be a new promising therapeutic approach in the process of improving Treg function in psoriasis.

Therapist-Reported Features of Exposure Tasks That Predict Differential Treatment Outcomes for Youth With Anxiety.

OBJECTIVE: Exposure tasks are recognized widely as a key component of cognitive-behavioral therapy (CBT) for child and adolescent anxiety. However, little research has examined specific exposure characteristics that predict outcomes for youth with anxiety and that may guide its application in therapy. METHOD: This study draws on a sample of 279 children and adolescents (48.4% male; 79.6% white) with a principal anxiety disorder who received 14 sessions of CBT, either alone or in combination with medication, through the Child/adolescent Anxiety Multimodal treatment Study (CAMS). The present study examines therapist-reported quantity, difficulty level, compliance, and mastery of exposure tasks as they related to CBT response (i.e., Clinical Global Impressions-Improvement ratings). Secondary treatment outcomes included reduction in anxiety symptom severity on the Pediatric Anxiety Rating Scale, global impairment measured via the Children's Global Assessment Scale, and parent-report of anxiety-specific functional impairment on the Child Anxiety Impairment Scale. RESULTS: Regression analyses indicated a dose-response relationship between therapist-reported quantity of exposure and independent evaluations of treatment outcome, with more time devoted to exposure linked to better outcomes. Similarly, greater time spent on more difficult (rather than mild or moderate) exposure tasks predicted better outcomes, as did therapist ratings of child compliance and mastery. CONCLUSION: The present findings highlight the importance of challenging children and adolescents with difficult exposure tasks and of collaborating to ensure compliance and mastery.

Developmental and clinical predictors of comorbidity for youth with obsessive compulsive disorder.

OBJECTIVE: To date, few studies of childhood obsessive compulsive disorder (OCD) have been adequately powered to examine patterns and predictors of comorbidity, despite the frequency with which it occurs. We address this gap, drawing on a large sample of youth with OCD who were systematically assessed through research and clinical programs in a university-based specialty program for children and adolescents with OCD. We examine patterns of comorbidity across different epochs of development and predict specific classes of OCD (comorbidity internalizing/externalizing/both) from key demographic and clinical variables that may be useful in guiding individualized treatment. METHOD: A total of 322 youths (mean age = 12.28, 53% male) were assessed using the Anxiety Disorders Interview Schedule (ADIS; Silverman and Albano, 1996), the Children's Yale Brown Obsessive Compulsive Scale (CYBOCS; Scahill et al., 1997) and other standardized measures. RESULTS: Consistent with prior research, 50% of youth met criteria for a co-occurring anxiety or depressive disorder. Rates of externalizing disorders were lower (16%). Developmental differences emerged such that older youth met criteria for a higher number of co-occurring disorders. As expected, adolescents in particular were more likely to have a co-occurring internalizing disorder compared to early or pre-adolescent peers. Surprisingly, they were also more likely to have a comorbid externalizing disorder. Developmental trends were particularly striking with respect to depression, with adolescents with OCD demonstrating a six-fold greater likelihood of co-occurring depressive disorder compared to younger counterparts. DISCUSSION: Clinical implications are discussed with eye toward tailoring interventions, particularly during the transition to adolescence when youth are at heightened risk for depression.

Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression.

Bullous pemphigoid (BP) is considered to be a humorally mediated autoimmune disease, but autoreactive T-cells and T-regulatory cells (Tregs) have also been implicated in this disease. Tregs and the programmed death-1 (PD-1) : programmed death ligand (PD-L) pathway are both critical in terminating immune response, and elimination of either can result in breakdown of tolerance and development of autoimmunity. We report a patient with metastatic malignant melanoma (MM), who underwent pembrolizumab (anti-PD-1) therapy following unsuccessful treatment with ipilimumab [anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4]. The patient developed BP with increasing serum titres of anti-BP180 IgG autoantibodies and increasing disease severity during pembrolizumab therapy. High doses of corticosteroids and methotrexate were needed to control the BP. Following the termination of pembrolizumab therapy, imaging showed complete regression of all metastatic sites. This result may indicate a crucial role for T-cell suppressive activity in controlling and preventing BP.

Distinguishing Fear Versus Distress Symptomatology in Pediatric OCD.

Prior research has identified OCD subtypes or "clusters" of symptoms that differentially relate to clinical features of the disorder. Given the high comorbidity between OCD and anxiety, OCD symptom clusters may more broadly associate with fear and/or distress internalizing constructs. This study examines fear and distress dimensions, including physical concerns (fear), separation anxiety (fear), perfectionism (distress), and anxious coping (distress), as predictors of previously empirically-derived OCD symptom clusters in a sample of 215 youth diagnosed with primary OCD (ages 7-17, mean age = 12.25). Self-reported separation fears predicted membership in Cluster 1 (aggressive, sexual, religious, somatic obsessions, and checking compulsions) while somatic/autonomic fears predicted membership in Cluster 2 (symmetry obsessions and ordering, counting, repeating compulsions). Results highlight the diversity of pediatric OCD symptoms and their differential association with fear, suggesting the need to carefully assess both OCD and global fear constructs that might be directly targeted in treatment.

Evidence-Based Assessment of Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric illness that often develops in childhood, affects 1%-2% of the population, and causes significant impairment across the lifespan. The first step in identifying and treating OCD is a thorough evidence-based assessment. This paper reviews the administration pragmatics, psychometric properties, and limitations of commonly used assessment measures for adults and youths with OCD. This includes diagnostic interviews, clinician-administered symptom severity scales, self-report measures, and parent/child measures. Additionally, adjunctive measures that assess important related factors (ie, impairment, family accommodation, and insight) are also discussed. This paper concludes with recommendations for an evidence-based assessment based on individualized assessment goals that include generating an OCD diagnosis, determining symptom severity, and monitoring treatment progress.

Segmental basal cell naevus syndrome caused by an activating mutation in smoothened.

Aberrant sonic hedgehog signalling, mostly due to PTCH1 mutations, has been shown to play a central role in the pathogenesis of basal cell carcinoma (BCC), as well as in basal cell naevus syndrome (BCNS). Mutations in smoothened (SMO) encoding a receptor for sonic hedgehog have been reported in sporadic BCCs but not in BCNS. We report a case with multiple BCCs, pits and comedones in a segmental distribution over the upper part of the body, along with other findings compatible with BCNS. Histopathologically, there were different types of BCC. A heterozygous mutation (c.1234C>T, p.L412F) in SMO was detected in three BCCs but not in peripheral blood lymphocytes or the uninvolved skin. These were compatible with the type 1 mosaic form of BCNS. The p.L412F mutation was found experimentally to result in increased SMO transactivating activity, and the patient responded to vismodegib therapy. Activating mutations in SMO may cause BCNS. The identification of a gain-of-function mutation in SMO causing a type 1 mosaic form of BCNS further expands our understanding of the pathogenesis of BCC, with implications for the treatment of these tumours, whether sporadic or inherited.