Explore the vast range of titles available.

Janus kinase (JAK) inhibitors are immunomodulatory agents with broad potential for use within dermatology. However, the US Food and Drug Administration has recently placed additional warning labels on JAK inhibitors given concern for an increased risk of major adverse cardiovascular events, malignancy, venous thromboembolism, and mortality. Here, we summarize recent efficacy and safety data of multiple JAK inhibitors including tofacitinib, upadacitinib, baricitinib, and abrocitinib. JAK inhibitors have high efficacy in treating psoriatic arthritis and atopic dermatitis, but carry an increased risk of venous thromboembolism and cardiovascular events relative to other approved treatments. Here, we provide current considerations on balancing the benefits of JAK inhibitors with potentially serious, but low-absolute risk, safety concerns.

Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation.

Smoking affects microcirculation by damaging endothelial cells and reducing blood flow. Vascular disease is also thought to contribute to the development of diabetic neuropathy, resulting in the decrease of nerve fiber density. The impact of nicotine on vasculature using optical coherence tomography angiography (OCT-A) has been extensively studied. We utilized an alternative method, reactive hyperemia OCT-A (RH-OCT-A), to provide a more complete visualization of microvasculature changes in the forearm of 5 old female smokers (mean age = 62.6yrs) and 7 young female smokers (mean age = 26.6yrs) compared against old ( n  = 17, mean age = 67.8yrs) and young ( n  = 22, mean age = 24.0yrs) nonsmoking populations. Intraepidermal nerve fiber densities (IENF) were collected from 6 old female smokers (mean age = 63.0yrs) and 12 young female smokers (mean age = 26.3yrs) and compared against 11 old female nonsmokers (mean age = 66.2yrs) and 13 young female nonsmokers (mean age = 24.2yrs). A trend was observed from vessel density measurements showing old smokers with the lowest value (15.7%), followed by old nonsmokers (16.4%), young smokers (18.8%), and finally young nonsmokers (18.9%). Additionally, the correlation within the smoking population between pack-year history and vessel density was stronger than the correlation between subject age and vessel density ( R = -0.53 vs. R = -0.42). Using RH-OCT-A, we show that smoking history is associated with lower vessel density and therefore suggestive of accelerated aging.

Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. We show that the cysteine protease cathepsin S activates MrgprC11 and evokes receptor-dependent scratching in mice. In contrast to its activation of conventional protease-activated receptors, cathepsin S-mediated activation of MrgprC11 did not involve the generation of a tethered ligand. We demonstrate further that different cysteine proteases selectively activate specific mouse and human Mrgpr family members. This expansion of our understanding by which proteases interact with G-protein-coupled receptors (GPCRs) redefines the concept of what constitutes a protease-activated receptor. The findings also implicate proteases as ligands to members of this orphan receptor family while providing new insights into how cysteine proteases contribute to itch. Sensory neurons that mediate histamine-independent itch express Mas-related G protein coupled receptors (Mrgprs). Here, Reddy et al. show that the cysteine protease cathepsin S cleaves and activates MrgpcrC11 without the generation of a tethered ligand, in contrast to other protease activated receptors.

Vulvar pruritus is an unpleasant sensation and frequent symptom associated with many dermatologic conditions, including infectious, inflammatory and neoplastic dermatoses affecting the female genitalia. It can lead to serious impairment of quality of life, impacting sexual function, relationships, sleep and self-esteem. In this review, common conditions associated with vulvar itch are discussed including atopic and contact dermatitis, lichen sclerosus, psoriasis and infectious vulvovaginitis. We review the potential physiologic, environmental and infectious factors that contribute to the development of vulvar itch and emphasize the importance of addressing their complex interplay when managing this disruptive and challenging symptom.

Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare disorders of heme biosynthesis characterized by severe cutaneous phototoxicity. Afamelanotide, an α-melanocyte-stimulating hormone analogue, is the only approved treatment for protoporphyria and leads to increased light tolerance and improved quality of life (QoL). However, published experience with afamelanotide in the US is limited. Methods: Here, we report on all adults who received at least one dose of afamelanotide at the Massachusetts General Hospital Porphyria Center from 2021 to 2022. Changes in the time to phototoxic symptom onset, QoL, and laboratory parameters were assessed before and during treatment with afamelanotide. Results: A total of 29 patients with protoporphyria were included, 26 of whom (72.2%) received ≥2 afamelanotide implants. Among the patients who received ≥2 implants, the median time to symptom onset following sunlight exposure was 12.5 min (IQR, 5–20) prior to the initiation of afamelanotide and 120 min (IQR, 60–240) after treatment (p < 0.001). Improvements in QoL during afamelanotide treatment were measured using two QoL tools, with good correlation observed between these two instruments. Finally, we found no improvements in the median levels of metal-free erythrocyte protoporphyrin, plasma protoporphyrin, or liver biochemistries during versus prior to the initiation of afamelanotide treatment. Conclusions: This study highlights a dramatic clinical benefit of afamelanotide in relation to light tolerance and QoL in protoporphyria, albeit without improvement in protoporphyrin levels or measures of liver function.

Janus kinase (JAK) inhibitors are immunomodulatory agents with broad potential for use within dermatology. However, the US Food and Drug Administration has recently placed additional warning labels on JAK inhibitors given concern for an increased risk of major adverse cardiovascular events, malignancy, venous thromboembolism, and mortality. Here, we summarize recent efficacy and safety data of multiple JAK inhibitors including tofacitinib, upadacitinib, baricitinib, and abrocitinib. JAK inhibitors have high efficacy in treating psoriatic arthritis and atopic dermatitis, but carry an increased risk of venous thromboembolism and cardiovascular events relative to other approved treatments. Here, we provide current considerations on balancing the benefits of JAK inhibitors with potentially serious, but low-absolute risk, safety concerns.Janus kinase (JAK) inhibitors are immunomodulatory agents with broad potential for use within dermatology. However, the US Food and Drug Administration has recently placed additional warning labels on JAK inhibitors given concern for an increased risk of major adverse cardiovascular events, malignancy, venous thromboembolism, and mortality. Here, we summarize recent efficacy and safety data of multiple JAK inhibitors including tofacitinib, upadacitinib, baricitinib, and abrocitinib. JAK inhibitors have high efficacy in treating psoriatic arthritis and atopic dermatitis, but carry an increased risk of venous thromboembolism and cardiovascular events relative to other approved treatments. Here, we provide current considerations on balancing the benefits of JAK inhibitors with potentially serious, but low-absolute risk, safety concerns.

Excoriation disorder is a psychocutaneous disorder characterized by repetitive skin-picking and associated with significant morbidity. Currently, epidemiological data in patients with excoriation disorder are lacking so we sought to characterize common patient demographics and comorbidities. We conducted a retrospective case-control study comparing 250 patients with excoriation disorder with 250 age-, race- and sex-matched controls identified between 2007 and 2019 at a single tertiary care center. We found that the majority of excoriation disorder patients were female (76%), Caucasian (82%) and unmarried (62%), with a mean age of 49 years. Compared to the matched controls, patients with excoriation disorder had increased odds of several psychiatric illnesses, including obsessive compulsive disorder (odds ratio (OR) 28.48, 95% confidence interval (CI): 1.68, 481.75), substance use disorder (OR 24.33, 95% CI: 5.81, 101.77), post-traumatic stress disorder (OR 8.23, 95% CI: 2.24, 129.40), depression (OR 8.19, 95% CI: 4.86, 13.80), bipolar disorder (OR 7.55, 95% CI: 2.22, 25.65), attention-deficit/hyperactivity disorder (OR 5.63, 95% CI: 1.62, 19.57), and anxiety (OR 5.01, 95% CI: 2.92, 8.62). Only a minority (42%) of patients were given psychiatry referrals and of those referred, a majority (64%) did not follow-up with psychiatry. The outcomes were also generally unfavorable as only 21% of patients experienced a resolution or improvement in their symptoms. This highlights the need for a multidisciplinary approach to manage patients with excoriation disorder, involving both dermatologists and psychiatrists.

Cryolipolysis is a noninvasive, skin cooling treatment for local fat reduction that causes prolonged hypoesthesia over the treated area. We tested the hypothesis that cryolipolysis can attenuate nociception of a range of sensory stimuli, including stimuli that evoke itch. The effects of cryolipolysis on sensory phenomena were evaluated by quantitative sensory testing (QST) in 11 healthy subjects over a period of 56 days. Mechanical and thermal pain thresholds were measured on treated and contralateral untreated (control) flanks. Itch duration was evaluated following histamine iontophoresis. Unmyelinated epidermal nerve fiber and myelinated dermal nerve fiber densities were quantified in skin biopsies from six subjects. Cryolipolysis produced a marked decrease in mechanical and thermal pain sensitivity. Hyposensitivity started between two to seven days after cryolipolysis and persisted for at least thirty-five days post treatment. Skin biopsies revealed that cryolipolysis decreased epidermal nerve fiber density, as well as dermal myelinated nerve fiber density, which persisted throughout the study. In conclusion, cryolipolysis causes significant and prolonged decreases in cutaneous sensitivity. Our data suggest that controlled skin cooling to specifically target cutaneous nerve fibers has the potential to be useful for prolonged relief of cutaneous pain and might have a use as a research tool to isolate and study cutaneous itch-sensing nerves in human skin.

IntroductionErythropoietic protoporphyria and X-linked protoporphyria, collectively referred to as the protoporphyrias, result in accumulation of protoporphyrin IX, causing severe cutaneous pain and, in a minority of patients, liver failure. Approximately half of patients with protoporphyria have microcytic hypochromic anemia, which may be related to reduced iron availability or decreased heme biosynthesis. Several reports have described mild thrombocytopenia in patients with protoporphyria as well, though the mechanism for this remains unknown. In this study, we characterize the relationship between erythrocyte metal-free protoporphyrin IX (PPIX) levels, platelet count, and iron status in patients with protoporphyria.MethodsWe analyzed hematologic parameters in patients with protoporphyria treated at the Mass General Brigham (MGB) hospital system. Patient-level data across multiple time points were collected. Generalized Estimating Equation (GEE) models with an identity link and Gaussian family distribution were performed to determine the association, accounting for within-participant associations. A separate analysis was performed using linear regression for a cohort of patients with protoporphyria in Sweden, with one value per patient.ResultsA total of 118 patients with protoporphyria were included in the analysis including 65 patients from MGB and 53 from the Swedish cohort. In the MGB cohort, the median PPIX level was 1482 ug/dl (min 265- max 4897, ref <20). A 1mg/dl increase in PPIX was associated with a 0.02 x109/L decrease in platelet count on average (p< 0.0001). This relationship was consistent when adjusting for alanine transaminase (ALT) and ferritin. There was no association between PPIX and ferritin (p = 0.57), PPIX and soluble transferrin receptor (p=0.31), or PPIX and hemoglobin (p =0.40). Higher PPIX levels were associated with lower MCV (p = 0.019) and higher ALT (p <0.0001). Similarly, in the Swedish cohort, a 1 mmol/L (ref <1.2) increase in PPIX was associated with a 1.4640 x109/L decrease in platelet count (p = 0.01224), a relationship that remained consistent when adjusting for ALT and ferritin. PPIX was not significantly associated with hemoglobin (p=0.102), ferritin (p=0.352), MCV (p=0.063), or ALT (p=0.068), but the trends for MCV and ALT were present in the same direction as for the US cohort.ConclusionIn this study of 118 patients with protoporphyria in the US and Sweden, we demonstrated a linear relationship between PPIX and platelet count that remained consistent when controlling for ALT and ferritin. The PPIX level was not associated with hemoglobin or markers of iron stores. Moving forward, we plan to present data for matched controls in the MGB cohort as well as data on the iron regulatory hormones, hepcidin and erythroferrone, in this group of patients.