ABSTRACT
BACKGROUND: Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. OBJECTIVES: To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. METHODS: We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2-16â years and unresponsive to potent topical treatment were randomized to either oral CyA (4â mg kg-1 daily) or MTX (0.4â mg kg-1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. RESULTS: In total, 103 participants were randomized (May 2016-February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD -5.69, 97.5% confidence interval (CI) -10.81 to -0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23-5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13-0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42-6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. CONCLUSIONS: Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation.
Subject(s)
Cyclosporine , Dermatitis, Atopic , Child , Humans , Adolescent , Cyclosporine/adverse effects , Methotrexate/adverse effects , Dermatitis, Atopic/drug therapy , Filaggrin Proteins , Odds Ratio , Treatment Outcome , Severity of Illness Index , Double-Blind MethodSubject(s)
Nevus, Spindle Cell/diagnosis , Remission, Spontaneous , Skin Neoplasms/diagnosis , Child, Preschool , Female , HumansABSTRACT
BACKGROUND: A 17-year-old boy on long-term immunosuppression following renal transplantation for chronic kidney disease (CKD), the result of dysplastic kidneys, initially presented with a swelling in his neck while attending hospital for an unrelated problem. A clinical diagnosis of tonsillitis was made, and he was treated with broad-spectrum antibiotics. Over a few days, his condition deteriorated, and he developed multiple vesicopustular skin lesions and required an emergency tonsillectomy due to respiratory distress. CASE DIAGNOSIS/TREATMENT: Histological investigation of the skin and tonsillar tissue suggested a viral aetiology, and subsequent electron microscopy and polymerase chain reaction (PCR) tissue examination proved disseminated cowpox infection. The family cat, which was reported as having self-resolving sores on its skin, was likely the source of the infection. The child failed to respond to antiviral treatment and succumbed to multiorgan failure within a month of admission. CONCLUSIONS: We report this case of fatal disseminated cowpox infection to highlight an increasing risk of this illness in the post-transplant population and to detail some unusual features not previously described, such as tonsillar involvement, disseminated skin lesions and multiorgan failure.
Subject(s)
Cowpox/virology , Kidney Transplantation/adverse effects , Adolescent , Anti-Bacterial Agents/therapeutic use , Cowpox/pathology , Cowpox virus/genetics , Fatal Outcome , Humans , Male , Multiple Organ Failure/etiology , Polymerase Chain Reaction , Renal Insufficiency, Chronic/surgery , Skin Diseases/etiology , Skin Diseases/virology , Tonsillitis/drug therapy , Transplant RecipientsABSTRACT
Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , DNA/genetics , Interleukin-1/biosynthesis , Keratinocytes/metabolism , Mutation , Psoriasis/genetics , Up-Regulation , Adaptor Proteins, Signal Transducing/metabolism , Aged , Autophagy , Cell Line , DNA Mutational Analysis , Female , Humans , Interleukin-1/genetics , Keratinocytes/pathology , Middle Aged , Psoriasis/metabolism , Psoriasis/pathology , Signal Transduction , Transcriptional ActivationABSTRACT
We describe a 72-year-old woman with striking cutaneous telangiectatic lesions that chronologically preceded presentation with cauda equina syndrome. Diffuse large B-cell lymphoma (DLBCL) was confirmed on skin biopsies from plaques on the abdominal wall and left ankle, the possibilities including primary cutaneous DLBCL leg-type or systemic DLBCL. We speculate that this clinical appearance may arise due to lymphatic or vascular congestion resulting from the dense lymphoid infiltrate in this case.
Subject(s)
Lymphoma, Large B-Cell, Diffuse/complications , Polyradiculopathy/etiology , Skin Neoplasms/complications , Skin/pathology , Telangiectasis/etiology , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Biopsy , Female , Humans , Immunohistochemistry , Lymphoma, Large B-Cell, Diffuse/chemistry , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/therapy , Polyradiculopathy/diagnosis , Predictive Value of Tests , Radiotherapy, Adjuvant , Skin/chemistry , Skin Neoplasms/chemistry , Skin Neoplasms/diagnosis , Skin Neoplasms/therapy , Telangiectasis/diagnosis , Treatment OutcomeSubject(s)
Brachial Plexus Neuropathies/complications , Hand Deformities, Acquired/etiology , Self Mutilation/etiology , Skin Ulcer/etiology , Thumb/injuries , Birth Injuries/complications , Bites, Human , Brachial Plexus Neuropathies/diagnosis , Delayed Diagnosis , Humans , Hypesthesia/etiology , Infant , Infant, Newborn , Male , Obstetrical Forceps/adverse effects , Thumb/innervation , Thumb/pathologyABSTRACT
Cutaneous lymphoid hyperplasia or pseudolymphoma is a usually benign inflammatory response that mimics lymphoma. Stimulation from foreign antigens introduced into the skin can induce this response. Scratches from pets are an effective mode of transmitting infections and inoculating foreign antigens into the skin. We report an unusual case of a child where cutaneous lymphoid hyperplasia presented as subcutaneous nodules at sites scratched by a pet cat.
Subject(s)
Cats , Pseudolymphoma/etiology , Skin Diseases/etiology , Amoxicillin-Potassium Clavulanate Combination/therapeutic use , Animals , Antigens/adverse effects , Azithromycin/therapeutic use , Child , Dermatologic Agents/therapeutic use , Female , Humans , Itraconazole/therapeutic use , Naphthalenes/therapeutic use , Pseudolymphoma/diagnosis , Pseudolymphoma/drug therapy , Pseudolymphoma/pathology , Radiography, Thoracic , Skin Diseases/diagnosis , Skin Diseases/drug therapy , Skin Diseases/pathology , TerbinafineABSTRACT
Transgrediens et progrediens palmoplantar keratoderma, known as Greither's syndrome, was originally described in 1952 and is characterized by diffuse keratoderma of the palms and soles, extending to the back aspects (transgrediens) and involving the skin over the Achilles' tendon. Patchy hyperkeratosis also develops on the shins, knees, elbows, and sometimes on the skin flexures. We describe two unrelated families affected with Greither's syndrome, in which the same dominant missense mutation gave rise to the amino acid change N188S in K1. The previously reported cases of Greither's syndrome showed phenotypic variability suggestive of different underlying gene defects. Our findings suggest that at least some cases of Greither's syndrome are caused by keratin mutations.