Brittany G. Craiglow

Killing Two Birds with One Stone: Oral Tofacitinib Reverses Alopecia Universalis in a Patient with Plaque Psoriasis

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Predictors of Early Adult Outcomes in Pediatric-Onset Obsessive-Compulsive Disorder

OBJECTIVE: The aim of this study was to determine the childhood clinical predictors of early adult outcomes in pediatric-onset obsessive-compulsive disorder (OCD) and to assess whether dimensional subtypes of OCD and the presence of comorbid tic symptoms influence long-term outcomes. METHODS: We conducted a longitudinal cohort study in which 45 of 62 eligible children with OCD were reassessed an average of 9 years later, in early adulthood. Main outcome measures included expert-rated, obsessive-compulsive (OC) symptom severity and time to remission of OC symptoms. Baseline clinical characteristics were evaluated in terms of their influence on OCD severity in adulthood and time to remission of OC symptoms. RESULTS: Forty-four percent of subjects were determined to have subclinical OC symptoms at the follow-up evaluation. The absence of a comorbid tic disorder and the presence of prominent hoarding symptoms were associated with the persistence of OCD symptoms. Female gender, earlier age at childhood assessment, later age of OCD onset, more-severe childhood OCD symptoms, and comorbid oppositional defiant disorder also were associated with persistence of OCD symptoms into adulthood. CONCLUSIONS: These results confirm that a significant proportion of treated children with OCD experience remission by adulthood. The presence of comorbid tics heralds a positive outcome, whereas primary hoarding symptoms are associated with persistent OCD.

Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed Therapy

IMPORTANCE Vitiligo is a common condition that is often emotionally devastating for patients. At present, no reliably effective treatments are available. OBSERVATIONS Recent advances in the understanding of the pathogenesis of vitiligo suggest that Janus kinase inhibitors may be a therapeutic option. We report a case of generalized vitiligo for which treatment with tofacitinib citrate, an oral Janus kinase 1/3 inhibitor, resulted in significant repigmentation. CONCLUSIONS AND RELEVANCE The results suggest that tofacitinib and other Janus kinase inhibitors may be effective in the treatment of vitiligo. Additional studies will be needed to confirm their efficacy and to explore their safety.

Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata

BACKGROUND Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined. METHODS This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome. RESULTS Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment. CONCLUSIONS At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease. TRIAL REGISTRATION ClinicalTrials.gov NCT02197455 and NCT02312882. FUNDING This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

Tofacitinib for the treatment of severe alopecia areata and variants: A study of 90 patients.

Background: Alopecia areata (AA) is a common autoimmune disorder. There are no reliably effective therapies for AA. Objective: We sought to evaluate the safety and efficacy of the Janus kinase 1/3 inhibitor, tofacitinib, in a series of patients over an extended period of time. Methods: This is a retrospective study of patients age 18 years or older with AA with at least 40% scalp hair loss treated with tofacitinib. The primary end point was the percent change in Severity of Alopecia Tool (SALT) score during treatment. Results: Ninety patients met inclusion criteria. Of 65 potential responders to therapy, defined as those with alopecia totalis or alopecia universalis with duration of current episode of disease of 10 years or less or alopecia areata, 77% achieved a clinical response, with 58% of patients achieving greater than 50% change in SALT score over 4 to 18 months of treatment. Patients with AA experienced a higher percent change in SALT score than did patients with alopecia totalis or alopecia universalis (81.9% vs 59.0%). Tofacitinib was well tolerated, and there were no serious adverse events. Limitations: The retrospective nature of the data, the relatively small number of patients, and lack of a control group are limitations. Conclusion: Tofacitinib should be considered for the treatment of severe AA, alopecia totalis, and alopecia universalis; tofacitinib dose response will be better defined by randomized controlled trials.

Tofacitinib for the treatment of alopecia areata and variants in adolescents

Background: There are no reliably effective therapies for alopecia areata (AA). Objective: We sought to evaluate the benefit and adverse effects of the Janus kinase 1/3 inhibitor, tofacitinib, in a series of adolescent patients with AA. Methods: We reviewed the records of 13 adolescent patients with AA treated with tofacitinib. Severity of disease was assessed using the Severity of Alopecia Tool (SALT). Adverse events were evaluated by laboratory monitoring, physical examinations, and review of systems. Results: Thirteen patients, aged 12 to 17 years, with AA were treated with tofacitinib. Nine patients experienced clinically significant hair regrowth. Median percent change in SALT score was 93% (mean 61%; 1%‐100%) at an average of 6.5 months of treatment. Adverse events were mild. Limitations: Limitations include the retrospective nature of the data, small sample size, and lack of a control group. Conclusion: Tofacitinib is a promising therapy for AA in adolescents. The use of tofacitinib and other Janus kinase inhibitors for the treatment of AA in this age group should be further evaluated in prospective clinical trials.

Poor fine‐motor and visuospatial skills predict persistence of pediatric‐onset obsessive‐compulsive disorder into adulthood

BACKGROUND Half of pediatric-onset OCD cases remit by adulthood. Studies have demonstrated that initial response to pharmacotherapy, age of onset, prominent hoarding symptoms, and the presence of comorbid tic disorders are associated with long-term outcome. Our goal was to examine the association between childhood performance on neuropsychological testing and persistence of OCD into adulthood. METHODS Twenty-four children with OCD were followed for an average of 7.5 years into early adulthood. Neuropsychological performance in childhood (<16 years) was measured. The battery included the Wechsler Intelligence Scale for Children (WISC-III), the Purdue pegboard test, the Rey-Osterreith Complex Figure Task (RCFT) and the Beery-Buktenica test of Visual Motor Integration (VMI). We hypothesized that deficits in fine-motor skills, visuospatial skills, and nonverbal memory as well as overall intelligence would be associated with adulthood outcome. We used a Cox proportional hazard model of survival analysis in which time to remission of OCD symptoms was the main outcome variable. RESULTS Poor childhood performance on the Purdue pegboard task and the block design subscale of WISC-III was associated with persistence of OCD symptoms into adulthood. IQ, VMI, and nonverbal memory performance did not predict significantly the persistence of OCD. CONCLUSIONS These results suggest that visuospatial and fine-motor skill deficits are predictive of poor long-term outcome in pediatric-onset OCD. Future longitudinal studies are needed to chart the course of these deficits relative to the course of symptoms in OCD and to determine whether the association of these neuropsychiatric deficits with long-term outcome is specific to pediatric-onset OCD or generalizes to other psychiatric disorders.

Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi.

TO THE EDITOR Woolly hair nevus (WHN) is a mosaic disorder characterized by distinct patterns of tightly curled scalp hair which can appear concurrently with epidermal nevi (EN) at other sites (Peteiro et al., 1989; Venugopal et al., 2012). Woolly hair is also found in congenital disorders resulting from mutations affecting diverse cellular components including intermediate filament, adherens junction, and signal transduction proteins (Harel and Christiano, 2012). Embryonic somatic mutation causes mosaic disorders which appear in patterns of ectodermal progenitor dorsovental migration. Somatic mutations causing mosaic disorders including Proteus syndrome (Lindhurst et al., 2011), port-wine stains (Shirley et al., 2013), and EN (Levinsohn et al., 2013; Sun et al., 2013) have been found using exome sequencing. Recognizing that exome sequencing would permit identification of mutations causing WHN, we ascertained two cases. Our first (WHN100, Figure 1a-d) was a 10 year-old girl without history of developmental delay who had regions of slightly curly hair over her occipital scalp from infancy which progressively curled with no scalp surface change and lie alongside areas of straight hair. She has hyperpigmented patches on her neck, trunk, and arms, with more keratotic lesions on her distal extremities, and acanthosis nigricans in both axillae. There was linear palmar keratoderma (PPK) and hyperkeratosis over most metacarpophalangeal and some proximal interphalangeal joints. Given concurrent PPK and woolly hair, clinical concern for Naxos or Carvajal syndromes led to regular cardiology evaluations that found no abnormalities. Figure 1 Clinical features of index cases with woolly hair nevi. On the scalp, woolly hair nevus presents with a portion of the scalp exhibiting patches of curly, thin, hair intermixed with regions of normal, straight hair, as observed in WHN100 and WHN101. On ... Our second case (WHN101, Figure 1e-h) was a 6 year-old girl whose hair developed at age one and consisted of a mixture of poker-straight hair and curly, thin hair. In infancy, she developed linear dyspigmentation on the right arm and trunk, which became more raised and scaly on the distal extremities over time. She had normal development, with no cardiac or ophthalmic abnormalities found on routine physical examination, cardiac MRI and serial electrocardiograms. Clinical suspicion of mosaic Naxos or Caravajal syndrome motivated clinical sequencing of DSP, DSC1, DSG1, JUP, PKP2, and TMEM43; no mutations were found. To determine the genetic basis of WHN, we performed paired whole exome sequencing of DNA isolated from affected tissue and blood in both cases (Supplementary Figure 2). Data was analyzed to identify somatic single nucleotide variants (SNVs), deletions and insertions (Supplementary Methods). A somatic heterozygous HRAS c.34G>A, p.G12S substitution was found in each (Figure 2a). There was no evidence of loss of heterozygosity (LOH) (Supplementary Figure 3) or secondary mutation somatic mutation, suggesting that HRAS mutation alone is sufficient to cause WHN. Sanger sequencing confirmed mutation presence in affected tissue (Figure 2b, c). To determine if this mutation causes woolly hair, we prepared DNA from hair bulbs of straight and curly hair obtained from affected individual WHN101, finding the HRAS p.G12S mutation in curly hair only (Figure 2d, Supplementary Figure 1). Figure 2 Somatic HRAS p.G12S mutation causes WHN. (a) In WHN100 and WHN101, exome sequencing of affected tissue and blood was performed. Tissue-specific SNVs are annotated bychromosome, position, base change, protein consequence, and numbers of reference and non-reference ... Consistent with somatic mosaicism in an epidermal progenitor, prior cases of WHN have been reported with concurrent keratinocytic epidermal nevi (KEN). KEN result from somatic mutations in HRAS, KRAS, PIK3CA, FGFR3, and NRAS (Hafner et al., 2012) including the HRAS p.G12S mutation found in WHN (Hafner et al., 2011). Furthermore, Costello syndrome (CS), in which patients present with developmental delay, high birth weight, feeding difficulties, failure to thrive, cardiac anomalies, and curly hair, results from germline heterozygous HRAS mutations, including p.G12S (Gripp and Lin, 2012; Siegel et al., 2012). The timing of somatic mutation during embryonic development determines extent of cutaneous involvement and presence of other systemic abnormalities (Moss et al., 1993). Notably, somatic activating HRAS mutations are found in most cases of nevus sebaceus (NS), a mosaic lesion which typically appears on the scalp and features alopecia, papillomatosis, and marked sebaceus hyperplasia (Groesser et al., 2012; Levinsohn et al., 2013; Sun et al., 2013). These features contrast with those of WHN in which hair is present but curly, and sebaceous hyperplasia is absent. Given that WHN and NS are both caused by somatic HRAS mutations, we hypothesize that their phenotypic divergence may derive from relative potency of the mutant allele with respect to MAP kinase activation. HRAS mutations in WHN and NS fall within the finger loop of HRAS, replacing glycine residues with larger amino acids which prevent GTP hydrolysis (Malumbres and Barbacid, 2003). Though comparison of the WHN p.G12S mutation and the common NS p.G13R mutation has not been performed, HRAS codon 12 serine substitutions have been shown to be less activating than arginine, aspartic acid or valine substitutions (Fasano et al., 1984). To evaluate the frequency of HRAS mutation in NS, we screened 116 archival scalp NS lesions for HRAS and KRAS mutation. We found 88 HRAS and 9 KRAS mutations. HRAS p.G13R was present in 85 NS and p.G12S was not found (Supplementary Table 2). In prior reports, 64 additional samples were screened, and HRAS p.G12S mutations were not found (Levinsohn et al., 2013; Sun et al., 2013). In one report, 3 specimens with HRAS p.G12S mutations were identified; in 2 there was a concurrent HRAS p.G13R mutation, and in one, the lesion was on the ear, a site at which it could be difficult to distinguish EN and NS (Groesser et al., 2012). These data combined with evidence from CS suggest that more strongly activating RAS mutations may cause the alopecia and sebaceous hyperplasia found in NS, and the more mildly activating p.G12S mutation causes woolly hair phenotypes. In summary, we find somatic HRAS c.34G>A, p.G12S mutation in affected tissue from two cases with mosaic woolly hair and EN. Consistent with reports of WHN and in KEN, the identified p.G12S mutation causes an EN phenotype on the body, but the finding of curly hair on the scalp suggests that WHN represents a mosaic RASopathy with phenotype determined by location, either due to distinct epidermal progenitor types or site-specific mesenchymal interactions. We hypothesize that in contrast to strongly activating RAS mutations found in NS which drive hair follicle progenitors toward sebocyte differentiation, the more weakly activating mutation found in WHN permits an intermediate phenotype with abnormal curly hair growth but without sebaceous hyperplasia.

Pediatric dermatology workforce shortage: Perspectives from academia

BACKGROUND The pediatric dermatology workforce has not been systematically evaluated since recent changes in board certification requirements. OBJECTIVE To quantify and characterize the workforce of academic pediatric dermatologists and examine issues related to training, hiring, and retention. METHODS Dermatology chairpersons and residency directors in the United States and Canada completed a 30-question survey. RESULTS Eighty of 132 programs (61%) responded to the survey. More than two thirds of programs (56/80) employed a pediatric dermatologist, and 34 programs were recruiting a pediatric dermatologist. The number of residents that pursue careers in pediatric dermatology is significantly associated with the number of pediatric dermatologists on faculty at their institution. LIMITATIONS Self-reported data, which may have been reflected by recall bias, and 61% response rate. CONCLUSIONS At a majority of academic centers, the current pool of pediatric dermatology faculty is neither adequate to meet academic nor clinical demands. Methods to increase exposure to pediatric dermatology among medical students and residents must be sought.

Ichthyosis in the newborn

The ichthyoses encompass a variety of genetic disorders marked by abnormal epidermal differentiation. The neonatal period is critical for patients with ichthyosis because of the risk for significant associated morbidity and mortality, with the majority of complications arising as a result of impaired barrier function. This article reviews presentations of ichthyosis in the neonate, outlines risks and complications, and provides strategies for management.