Safety of dermatologic medications in pregnancy and lactation: An Update - Part I: Pregnancy.

The breadth of therapeutic options for the management of dermatologic skin conditions continues to expand rapidly as exemplified by biologics and small molecule drug development. While dermatologists and healthcare providers are aware of the underlying mechanisms and indications for these therapeutics, there is a recognized practice gap due to an incomplete understanding of the safety of these medications in women of childbearing age during the prepartum, antepartum and postpartum phases. Although a two-part continuing medical education review was published regarding the prescribing practices and safety profiles of these new therapeutics in women of childbearing age while pregnant or lactating in 20141,2, many new medications have been approved since then. Herein, we will update the safety of dermatologic therapies during pregnancy and Part II will review the safety of medications during lactation.

Safety of dermatologic medications in pregnancy and lactation: An Update - Part II: Lactation.

Multiple recently approved medications have been added to our treatment armamentarium for various dermatologic conditions. Herein, we have reviewed the literature, consolidated available safety data, and offered recommendations based upon available evidence as a reference guide for clinicians treating patients for dermatologic conditions during lactation.

The First In-Human Application of Continuous Low-Irradiance Phototherapy for Chronic Wounds: A Pilot Study.

BACKGROUND: Polymicrobial colonization and resultant biofilm formation significantly impair the process of wound healing. Stagnant tissue repair processes predispose patients to serious complications including systemic infection and limb amputation. Continuous Low-Irradiance Phototherapy (CLIP) is a novel therapeutic approach that delivers blue light at low irradiance for extended periods of time. Bench and preclinical work in the literature indicates that 405 nm light avoids thermal injury of healthy tissue, promotes a cytokine milieu favoring re-epithelialization and angiogenesis, and prevents bacterial and biofilm growth.  Objective: This is the first in-human evaluation of a technology that delivers continuous low-irradiance 405 nm light to chronic wounds. The objective of this study was to determine the safety, feasibility, and ergonomics of this device for the treatment of chronic wounds in adult human subjects. This was not a randomized study to determine device efficacy, although data on outcome were collected. METHODS: In this prospective observational pilot study, participants received the intervention 24 hours per day, 7 days per week, for 4 weeks. Cohort I was conducted from December 2018 to March 2019, with Cohorts II and III ongoing. 25 study participants were recruited by referral (Cohort I: 5 participants, Cohort II: 10 participants, Cohort III: 10 participants). Our primary endpoint was to monitor for safety, assess usability by nurses and physicians, and evaluate patient comfort. The secondary endpoint, although not randomized nor directly compared with standard intervention, was the percentage area reduction (PAR) of the wound.  Results: No adverse events or subject discomfort occurred with the CLIP intervention. The staff treating the study participants reported no ergonomic or compliance issues with the use of the device. The device received high scores in categories assessing practicality and ease of use. There was an average PAR of 29% (SD = 0.42).  Conclusion: This study serves as the first in-human evaluation of extended low-irradiance 405 nm light for chronic wound therapy. The device appears safe and easy to use and had no compliance issues in the outpatient setting. Study participants who received CLIP without interruption saw either partial or complete reduction in wound area.  J Drugs Dermatol. 2023;22(11):1111-1117     doi:10.36849/JDD.7206.

Aberrant Bone Regulation in Albright Hereditary Osteodystrophy dueto Gnas Inactivation: Mechanisms and Translational Implications.

PURPOSE OF REVIEW: This review highlights the impact of Gnas inactivation on both bone remodeling and the development of heterotopic subcutaneous ossifications in Albright hereditary osteodystrophy (AHO). Here we discuss recent advancements in understanding the pathophysiologic mechanisms of the aberrant bone development in AHO as well as potential translational implications. RECENT FINDINGS: Gnas inactivation can regulate the differentiation and function of not only osteoblasts but also osteoclasts and osteocytes. Investigations utilizing a mouse model of AHO generated by targeted disruption of Gnas have revealed that bone formation and resorption are differentially affected based upon the parental origin of the Gnas mutation. Data suggest that Gnas inactivation leads to heterotopic bone formation within subcutaneous tissue by changing the connective tissue microenvironment, thereby promoting osteogenic differentiation of tissue-resident mesenchymal progenitors. Observed variations in bone formation and resorption based upon the parental origin of the Gnas mutation warrant future investigations and may have implications in the management and treatment of AHO and related conditions. Additionally, studies of heterotopic bone formation due to Gnas inactivation have identified an essential role of sonic hedgehog signaling, which could have therapeutic implications not only for AHO and related conditions but also for heterotopic bone formation in a wide variety of settings in which aberrant bone formation is a cause of significant morbidity.

Hair follicle-resident progenitor cells are a major cellular contributor to heterotopic subcutaneous ossifications in a mouse model of Albright hereditary osteodystrophy.

Heterotopic ossifications (HOs) are the pathologic process by which bone inappropriately forms outside of the skeletal system. Despite HOs being a persistent clinical problem in the general population, there are no definitive strategies for their prevention and treatment due to a limited understanding of the cellular and molecular mechanisms contributing to lesion development. One disease in which the development of heterotopic subcutaneous ossifications (SCOs) leads to morbidity is Albright hereditary osteodystrophy (AHO). AHO is caused by heterozygous inactivation of GNAS , the gene that encodes the α-stimulatory subunit (Gα s ) of G proteins. Previously, we had shown using our laboratory's AHO mouse model that SCOs develop around hair follicles (HFs). Here we show that SCO formation occurs due to inappropriate expansion and differentiation of HF-resident stem cells into osteoblasts. We also show in AHO patients and mice that Secreted Frizzled Related Protein 2 ( SFRP2) expression is upregulated in regions of SCO formation and that elimination of Sfrp2 in male AHO mice exacerbates SCO development. These studies provide key insights into the cellular and molecular mechanisms contributing to SCO development and have implications for potential therapeutic modalities not only for AHO patients but also for patients suffering from HOs with other etiologies.

Atypical Wells syndrome successfully treated with dupilumab.

Wells syndrome, also referred to as eosinophilic cellulitis, is a rare and often sporadic inflammatory skin condition whose aetiology remains uncertain. Clinically, this condition presents as a collection of erythematous, oedematous, and tender skin lesions most often affecting the extremities and trunk that can mimic cellulitis. Histologically, Wells syndrome is characterised by inflammatory changes and eosinophilic infiltration of the dermis with the absence of underlying infection, thereby distinguishing it from cellulitis. Due to the rarity of this syndrome and its ambiguous presentation, there remains to be a definitive strategy for treatment. Recent case reports have documented varying success and recurrence with the use of oral and topical corticosteroids, antifungals, antibiotics, immunosuppressants and antihistamines. Here, we report a unique case of progressively worsening neutrophilic-rich Wells syndrome on the vertex of the scalp that was successfully treated with a combination of dupilumab and oral corticosteroids.

Prevalence of Chiari malformation type 1 is increased in pseudohypoparathyroidism type 1A and associated with aberrant bone development.

BACKGROUND: Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with multi-hormone resistance and aberrant craniofacial and skeletal development among other abnormalities. Chiari malformation type 1 (CM1), a condition in which brain tissue extends into the spinal canal when the skull is too small, has been reported in isolated cases of PHP1A. It has been hypothesized to be associated with growth hormone (GH) deficiency. Given the adverse clinical sequelae that can occur if CM1 goes unrecognized, we investigated the previously undetermined prevalence of CM1, as well as any potential correlations with GH status, given the known increased prevalence of GH deficiency in PHP1A. We also investigated these metrics for low lying cerebellar tonsils (LLCT), defined as tonsillar descent less than 5 mm below the foramen magnum. In addition, we investigated possible correlations of CM1/LLCT with advanced hand/wrist bone ages and craniofacial abnormalities known to occur in PHP1A to determine whether premature chondrocyte differentiation and/or aberrant craniofacial development could be potential etiologies of CM1/LLCT through both human studies and investigations of our AHO mouse model. METHODS: We examined patients with PHP1A in our clinic and noticed CM1 more frequently than expected. Therefore, we set out to determine the true prevalence of CM1 and LLCT in a cohort of 54 mutation-confirmed PHP1A participants who had clinically-indicated brain imaging. We examined potential correlations with GH status, clinical features, biological sex, genotype, and hand/wrist bone age determinations. In addition, we investigated the craniofacial development in our mouse model of AHO (Gnas E1+/-m) by histologic analyses, dynamic histomorphometry, and micro-computerized tomographic imaging (MCT) in order to determine potential etiologies of CM1/LLCT in PHP1A. RESULTS: In our cohort of PHP1A, the prevalence of CM1 is 10.8%, which is at least 10-fold higher than in the general population. If LLCT is included, the prevalence increases to 21.7%. We found no correlation with GH status, biological sex, genotype, or hand/wrist bone age. Through investigations of our Gnas E1+/-m mice, the correlate to PHP1A, we identified a smaller cranial vault and increased cranial dome angle with evidence of hyperostosis due to increased osteogenesis. We also demonstrated that there was premature closure of the spheno-occipital synchondrosis (SOS), a cartilaginous structure essential to the development of the cranial base. These findings lead to craniofacial abnormalities and could contribute to CM1 and LLCT development in PHP1A. CONCLUSION: The prevalence of CM1 is at least 10-fold higher in PHP1A compared to the general population and 20-fold higher when including LLCT. This is independent of the GH deficiency that is found in approximately two-thirds of patients with PHP1A. In light of potential serious consequences of CM1, clinicians should have a low threshold for brain imaging. Investigations of our AHO mouse model revealed aberrant cranial formation including a smaller cranium, increased cranial dome angle, hyperostosis, and premature SOS closure rates, providing a potential etiology for the increased prevalence of CM1 and LLCT in PHP1A.

Parental Origin of Gsα Inactivation Differentially Affects Bone Remodeling in a Mouse Model of Albright Hereditary Osteodystrophy.

Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alpha-stimulatory subunit of heterotrimeric G proteins (Gsα) in addition to NESP55 and XLαs due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally-inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through G protein-coupled receptors (GPCRs) requiring Gsα (eg, parathyroid hormone [PTH], thyroid-stimulating hormone [TSH], growth hormone-releasing hormone [GHRH], calcitonin) and severe obesity. Paternally-inherited GNAS mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue-specific reduction of paternal Gsα expression. Previous reports in mice have shown loss of Gsα causes osteopenia due to impaired osteoblast number and function and suggest that AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal-increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized our laboratory's AHO mouse model to address whether Gsα heterozygous inactivation differentially affects bone remodeling based on the parental inheritance of the mutation. We identified fundamental distinctions in bone remodeling between mice with paternally-inherited (GnasE1+/-p) versus maternally-inherited (GnasE1+/-m) mutations, and these findings were observed predominantly in female mice. Specifically, GnasE1+/-p mice exhibited reduced bone parameters due to impaired bone formation and enhanced bone resorption. GnasE1+/-m mice, however, displayed enhanced bone parameters due to both increased osteoblast activity and normal bone resorption. These in vivo distinctions in bone remodeling between GnasE1+/-p and GnasE1+/-m mice could potentially be related to changes in the bone microenvironment driven by calcitonin-resistance within GnasE1+/-m osteoclasts. Further studies are warranted to assess how Gsα influences osteoblast-osteoclast coupling. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Antimicrobial Efficacy of Continuous Low-Irradiance Phototherapy Against Multidrug-Resistant Organisms.

Objective: The objective of this study is to report on the bactericidal effects of blue light administered at low irradiance for extended periods of time. Background: Multidrug-resistant organisms (MDROs) utilize biofilms that can limit the efficacy of antibiotics, causing infection and impaired wound healing. Unlike high-energy systems, continuous low-irradiance phototherapy (CLIP) avoids thermal injury of healthy tissue and can be delivered for extended periods. Methods: Four MDRO species, two of which contained different antibiotic resistance genes, were exposed to 405 nm irradiation in vitro. The microbes were incrementally exposed to increasing dose-rates (irradiance; mW/cm2) over a 24-h time period. Cell viability and biomass reduction assays were conducted to quantify the antibacterial/antibiofilm effects. Primary human dermal fibroblasts were also exposed to CLIP to assess whether these dose-rates would impair cell viability or proliferation. Results: CLIP exposure utilizing irradiances as low as 2.78 mW/cm2 delivered over 24 h resulted in a >3.0-log (>99.9%) and >2.0-log (>99.0%) microbial load reduction when organisms were grown in planktonic and biofilm-encapsulated conditions, respectively. Crystal violet biofilm assays revealed destruction of extracellular biofilm architecture following CLIP exposure. Human fibroblast viability and proliferation were unaffected by CLIP. Conclusions: This is the first report demonstrating the antimicrobial efficacy of CLIP for MDROs found in infected wounds. CLIP did not compromise cultured human fibroblast growth and survival. This study demonstrated that very low fluence rates (irradiances) delivered over extended periods are potently antimicrobial. There is translational potential for CLIP to be fabricated as a wearable device that would enable continuous ambulatory care of wounds.

Improving access to medicines via the Health Impact Fund in India: a stakeholder analysis.

BACKGROUND: In India, 50-65% of the population face difficulties in accessing medicines. The Health Impact Fund (HIF) is a novel proposal whereby pharmaceutical companies would be paid based on the measured global health impact of their drugs. We conducted a key stakeholder analysis to explore access to medicines in India, acceptability of the HIF and potential barriers and facilitators at policy level. OBJECTIVES: To conduct a stakeholder analysis of the HIF in India: to determine key stakeholder views regarding access to medicines in India; to evaluate acceptability of the HIF; and to assess potential barriers and facilitators to the HIF as a policy. METHODS: In New Delhi, we conducted semi-structured interviews. There was purposive recruitment of participants with snowball sampling. Transcribed data were analysed using stakeholder analysis frameworks and directed content analysis. RESULTS: Participation rate was 29% (14/49). 14 semi-structured interviews were conducted among stakeholders in New Delhi. All participants highlighted access to medicines as a problem in India. There were mixed views about the HIF in terms of relevance and scaleability. Stakeholders felt it should focus on diseases with limited or no market and potentially incorporate direct investment in research. CONCLUSIONS: First, access to medicines is perceived to be a major problem in India by all stakeholders, but affordability is just one factor. Second, stakeholders despite considerable support for the idea of the HIF, there are major concerns about scaleability, generalisability and impact on access to medicines. Third, the HIF and other novel drug-related health policies can afford to be more radical, e.g. working outside the existing intellectual property rights regime, targeting generic as well as branded drugs, or extending to research and development. Further innovations in access to medicines must involve country-specific key stakeholders in order to increase the likelihood of their success.