A phase 2, open-label study of single-dose dupilumab in children aged 6 months to <6 years with severe uncontrolled atopic dermatitis: pharmacokinetics, safety and efficacy.

BACKGROUND: Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6-17 years) with moderate-to-severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk-benefit profile in younger children remains a significant unmet need. OBJECTIVES: To determine the pharmacokinetics, safety and efficacy of single-dose dupilumab in children with severe AD aged ≥6 months to <6 years. METHODS: This open-label, multicenter, phase 2, sequential, two-age cohort, two-dose level study (LIBERTY AD PRE-SCHOOL; NCT03346434) included an initial cohort of older children aged ≥2 to <6 years, followed by a younger cohort aged ≥6 months to <2 years. Pharmacokinetic sampling, safety monitoring and efficacy assessments were performed during the 4-week period after a single subcutaneous injection of dupilumab, in two sequential dosing groups (3 mg/kg, then 6 mg/kg). The use of standardized, low-to-medium potency topical corticosteroids was allowed. RESULTS: Forty patients were enrolled (20/age cohort, 10/dose level within a cohort) between December 20, 2017 and July 22, 2019. Within each age cohort, pharmacokinetic exposures after a single injection of dupilumab increased in a greater than dose-proportional manner. At week 3, treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity Index by -44.6% and -49.7% (older cohort) and -42.7% and -38.8% (younger cohort), and mean Peak Pruritus NRS scores by -22.9% and -44.7% (older cohort) and -11.1% and -18.2% (younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished in both age groups, particularly with the lower dose. The safety profile was comparable to that seen in adults, adolescents and children. CONCLUSIONS: Single-dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of AD. Slightly better responses were seen in older than younger children. The pharmacokinetics of dupilumab were non-linear, consistent with previous studies in adults and adolescents.

The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.

The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.

Management of warts and molluscum in adolescents.

Warts continue to be a therapeutic challenge, especially when they are numerous or widespread; in contrast, treatment of molluscum is comparatively more successful. A single, most effective treatment for either infection has not been defined. Conventional methods attempt to non-specifically destroy infected tissue. Most of these procedures are painful and require multiple treatments or compliance with daily application of a medication. The efficacy of destructive techniques has not been verified in placebo-controlled clinical trials and success rates reported in uncontrolled studies are difficult to interpret and often no better than that those achieved with a placebo. Alternative pharmacological approaches are aimed at stimulating immunologic or antiviral responses. Further study is needed to establish efficacy of these treatments.

What's new in human papillomavirus infection.

Warts continue to be a therapeutic challenge, especially widespread warts on children. A single, most effective treatment has not been defined. Conventional methods attempt to nonspecifically destroy infected tissue. Most of these procedures are painful, poorly tolerated by children, and often require multiple treatments. The efficacy of destructive techniques is impossible to verify in controlled clinical trials. Uncontrolled success rates are suboptimal and often no better than that seen with placebos. Alternative pharmacologic approaches have been designed to stimulate immunologic responses or provide anti-viral activity. Further study is needed to establish efficacy of these treatments.

Hair removal using topical suspension-assisted Q-switched Nd:YAG and long-pulsed alexandrite lasers: A comparative study.

BACKGROUND: The use of lasers for removal of unwanted hair has been shown to be effective in temporarily controlling hair growth. Several lasers are currently utilized for this purpose. OBJECTIVE: This study evaluates the short-term effectiveness and discomfort levels of the long-pulsed alexandrite laser and the topical suspension-assisted Q-switched Nd:YAG laser in a side-by-side comparison. METHODS: Fifteen subjects were treated in the bilateral hair-bearing axilla, using one treatment with the alexandrite laser for the right and two treatments with the topical suspension-assisted Nd:YAG laser for the left. Reduction in hair regrowth was measured at 2 and 3 months following the first treatment by comparing the terminal hair count to the baseline values. Patients rated their pain on a scale of 0-10 immediately following the first treatment at each site. RESULTS: The mean percentage reduction in hair regrowth 2 months following alexandrite laser treatment was 55% and 73% for the Nd:YAG laser-treated regions. After 3 months, alexandrite laser-treated patients showed a reduction of 19%, while Nd:YAG laser-treated patients showed a 27% reduction. Patients reported average pain values of 8 and 4 for the long-pulsed alexandrite and Nd:YAG laser sites, respectively. All differences were significant. CONCLUSION: While the design of this study makes it difficult to compare the relative effectiveness of the lasers, both systems evaluated were shown to delay hair growth and provide patients with a satisfactory treatment.

Cimetidine therapy for recalcitrant warts in adults: is it any better than placebo?

Three open-label, uncontrolled studies have documented successful treatment of warts with cimetidine, whereas two placebo-controlled, double-blind studies and two open-label comparative trials have failed to demonstrate efficacy. This double-blind, placebo-controlled study was designed with stringent enrollment and outcome criteria to minimize the confounding issue of spontaneous remission. Efficacy was not statistically superior to that of placebo, but a trend toward efficacy was suggested for younger subjects.

Selective antibody deficiency to bacterial polysaccharide antigens in patients with Netherton syndrome.

Three patients with Netherton syndrome, recurrent sinopulmonary infections, and humoral immune deficiency are described. Although quantitative serum immunoglobulin levels were generally normal, two patients had selective antibody deficiency to bacterial polysaccharide antigens, one associated with IgA-IgG-2 deficiency. A third patient had an antibody deficiency to protein antigens. This is the first report, to our knowledge, that describes antibody deficiency in patients with Netherton syndrome. This finding demonstrates the importance of evaluating functional antibody responses to both protein and bacterial polysaccharide antigens and not relying on IgG subclass determination.

Skin care practices in the neonatal nursery: a clinical survey.

OBJECTIVE: To survey the details of skin care practices in a sample of level I, II, and III nurseries in the United States. DESIGN: A survey conducted by written questionnaire, personal inspection, and phone contact. PARTICIPANTS: Information was obtained from staff physicians and nurses about routine neonatal skin care practices, including bathing, cord care, emollient use, diapering, use of antimicrobial skin preparations, management of intravenous infiltration, approach to diaper rash, and methods used to minimize transcutaneous water loss. SETTING: Fifteen nurseries from twelve hospitals in four states were surveyed. RESULTS: Among the nurseries surveyed, we found no uniform approach to skin care. Only two individual maneuvers were consistently performed in all the nurseries: criteria for bathing and skin antisepsis with povidone-iodine. Other than these, a wide range of practices and products were used, some with a high ratio of risk and/or cost to benefit. CONCLUSION: A better understanding of the principles of infant skin care and a more uniform approach to skin care in the neonatal nursery can minimize risks and costs to this special population of patients.

The natural history of condyloma in children.

BACKGROUND: Condyloma acuminatum, an infection caused by human papillomavirus (HPV), has become one of the most common sexually transmitted diseases. Correspondingly, anogenital warts are more frequently diagnosed in children. Twenty-five years ago a landmark prospective study showed that untreated common cutaneous warts in children spontaneously regress within 2 years in two thirds of cases, but a similar study of condyloma has not been published. Several treatment options are available for condyloma in adults; none have been studied or approved by the US Food and Drug Administration for treatment of children. OBJECTIVE: Our purpose was to review a cohort of children with condyloma to determine the natural history. METHODS: Of 75 originally identified subjects with condyloma, 41 qualified for further retrospective or prospective evaluation, including distribution of lesions, duration of disease, gender, and treatment, if any. RESULTS: Overall, condylomas in 31 of 41 children (76%) experienced resolution. Spontaneous resolution occurred within 5 years in 22 of 41 subjects (54%), including 6 of 8 (75%) who never received treatment, and 16 of 33 (49%) in whom treatment failed. In 9 of 33 treated children (27%), resolution occurred during treatment. Girls presented three times more often than boys and resolution occurred comparatively more often in girls. CONCLUSION: Spontaneous resolution of pediatric condyloma occurred in more than half of our subjects. Nonintervention is a reasonable initial approach to managing venereal warts in children.

Neonatal skin and skin care.

Infant skin differs from adult skin in several ways. These important differences place infants at increased risk for fluid electrolyte imbalance, thermal instability, skin damage, percutaneous infection, and percutaneous toxicity from topically applied agents. This article includes a review of skin development, as well as the details of current skin care practices in the neonatal nursery. A better understanding of the principles of infant skin care and a more uniform approach to skin care in the neonatal nursery can minimize risks and costs to this special population of patients.

Chronic recurrent multifocal osteomyelitis preceding pyoderma gangrenosum and occult ulcerative colitis in a pediatric patient.

Chronic recurrent multifocal osteomyelitis (CRMO) is a clinicopathologic entity of unknown origin mainly affecting children and young adults. It shares many clinical features with pyoderma gangrenosum (PG), an uncommon ulcerating inflammatory disorder of the dermis and underlying subcutaneous fat. Both conditions are chronic and relapsing, and have been associated with inflammatory bowel disease (IBD). The diagnoses are made by exclusion. Histology is nonspecific and cultures are negative. There has been only one previous report of both conditions occurring in the same patient. Here we describe the second case, a 12-year-old girl who developed pyoderma gangrenosum in direct continuity to an underlying CRMO lesion of the right anterior tibia. Occult ulcerative colitis (UC) was subsequently discovered.

Anogenital skin diseases of childhood.

Evaluation of anogenital lesions in children is a challenging problem. The differential diagnosis includes a spectrum of traumatic, infectious, neoplastic, and genetic disorders. The possibility of sexual abuse should always be considered and investigated as indicated. A systematic work-up will expedite the correct diagnosis and limit unnecessary anxiety for parents, children, and physicians. Referral to a center that provides specialized service for the evaluation and treatment of these disorders may be indicated.

Anogenital warts in children.

Evaluation and treatment of pediatric condylomata acuminata are challenging problems. Careful and thorough evaluation for the possibility of sexual abuse is mandatory in all cases. New molecular techniques of HPV DNA detection and typing have not proved helpful in determining the source of the infection but may assist in identifying children who are at risk for the development of carcinoma. Ideal therapy does not exist; non-intervention may be the most appropriate choice for the majority of patients who carry low-risk viral types. Many unanswered questions remain regarding the biology and epidemiology of HPV in children and adults. Clinical and basic science research specifically designed to address the concerns of the pediatric age group is urgently needed.

Chronic recurrent multifocal osteomyelitis: an evolving clinical and radiological spectrum.

OBJECTIVE: To describe unusual clinical and radiological features in patients with chronic recurrent multifocal osteomyelitis (CRMO). DESIGN AND SUBJECTS: Based on radiographic and microscopic findings, three patients were prospectively diagnosed as having chronic recurrent multifocal osteomyelitis (CRMO). They form the basis of this report because of either the unusualness of the clinical presentation, hitherto undescribed associated diseases or the unusual age of presentation and sites of lesions. RESULTS: One patient developed pyoderma gangrenosum at the site of one of the skeletal lesions and then went on to develop ulcerative proctitis. A second patient presented with a soft tissue mass, which on MRI mimicked a sarcoma. The final patient presented with lesions in the wrist and phalanges of the toes at the unusual age of 38. None of the patients was treated with steroids or antibiotics for the skeletal lesions. Steroids were administered to one patient for treatment of pyoderma gangrenosum. CONCLUSIONS: The pattern and distribution of skeletal lesions in CRMO are well recognized in the pediatric age group. The unusual clinical and/or radiological features discussed herein suggests that this is a disease that continues to evolve with a broader spectrum of features than recognized.

Cutaneous congenital candidiasis: a case report.

Candida albicans is a frequent pathogen of the female genital tract, especially during pregnancy. Congenital candidiasis can occur as cutaneous or disseminated infection. We report a case of congenital cutaneous candidiasis, which may occur more frequently than is indicated by the literature. This is followed by a discussion of the pathogenesis, clinical presentation, diagnosis, and treatment of this infection.

Incontinentia pigmenti: transmission from father to daughter.

Incontinentia pigmenti (IP) is a well-described genodermatosis that occurs almost exclusively in females. IP is characterized by a distinctive skin eruption and a variable presence of multisystem abnormalities. Pedigree analysis is most consistent with an X-linked dominant trait that is lethal in males. However, 27 reports of IP in males have been published, excluding four patients who had Klinefelter's syndrome. It has usually been assumed that these rare affected males survive because of genetic mosaicism. Mosaic inheritance of IP is also strongly supported by the characteristic distribution of skin findings along Blaschko's lines. Only one case of father-to-daughter transmission has been previously reported. We report a second case of father-to-daughter transmission of IP. Chromosomal analysis of blood and fibroblasts from the father failed to provide evidence of genetic mosaicism.