Efficacy and safety of topical minocycline foam (FMX101 4%) in treatment of Chinese subjects with moderate-to-severe facial acne vulgaris: A phase 3, multi-centre, randomized, double-blind, vehicle-controlled study.

BACKGROUND: FMX101 4%, as a topical foam formulation of minocycline, has been approved by US Food and Drug Administration for the treatment of moderate-to-severe acne vulgaris (AV). OBJECTIVE: To evaluate the efficacy and safety of FMX101 4% in treating Chinese subjects with moderate-to-severe facial AV. METHODS: This was a multi-centre, randomized, double-blind, vehicle-controlled phase 3 study in Chinese subjects with moderate-to-severe AV. Eligible subjects were randomized 2:1 to receive either FMX101 4% or vehicle foam treatment for 12 weeks. The primary efficacy endpoint was the change in inflammation lesion count (ILC) from baseline at week 12. The key secondary endpoint was the treatment success rate according to Investigator's Global Assessment (IGA) at week 12. RESULTS: In total, 372 subjects were randomized into two groups (FMX101 4% group, n = 248; vehicle group, n = 124). After 12 weeks treatment, the reduction in ILC from baseline was statistically significant in favour of FMX101 4%, compared with vehicle foam (-21.0 [0.08] vs. -12.3 [1.14]; LSM [SE] difference, -8.7 [1.34]; 95% CI [-11.3, -6.0]; p < 0.001). FMX101 4% treatment yielded significantly higher IGA treatment success rate at week 12 as compared to the control treatment (8.06% vs. 0%). Applying FMX101 4% also resulted in significant reduction in noninflammatory lesion count (nILC) versus vehicle foam at week 12 (-19.4 [1.03] vs. -14.9 [1.47]; LSM [SE] difference, -4.5 [1.74]; 95% CI [-8.0, -1.1]; p = 0.009). Most treatment-emergent adverse events (TEAEs) were mild-to-moderate in severity, and no treatment-related treatment-emergent serious adverse event (TESAE) occurred. Thus, FMX101 4% was considered to be a safe and well-tolerated product during the 12-week treatment period. CONCLUSION: FMX101 4% treatment for 12 weeks could lead to significantly reduced ILC and nILC, and improved IGA treatment success rate in Chinese subjects with moderate-to-severe facial AV. It also showed a well acceptable safe and tolerability profile.

Cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes.

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.

Mupirocin blocks imiquimod-induced psoriasis-like skin lesion by inhibiting epidermal isoleucyl-tRNA synthetase.

BACKGROUND: The Isoleucyl-tRNA synthetase (IARS) catalyzes isoleucine to the corresponding tRNA, maintaining the accuracy of gene translation. Its role in psoriasis has been not investigated so far. In this study, we aimed to investigate the mechanisms underlying the efficacy of IARS inhibitor, mupirocin, treatment for psoriasis. METHODS: The expression of IARS was determined by immunofluorescence, Western blot and qRT-PCR in normal healthy control- and psoriatic human skin. An imiquimod (IMQ) -induced psoriasis-like skin disease model was used to study the phenotypes changed by an IARS inhibitor, mupirocin (MUP). Endotypes were analyzed by RNA-seq, R&D Luminex multi-factor technique, ELISA, immunofluorescence and flow cytometry. Additionally, the effect of MUP on epidermal keratinocytes (KCs) were conducted in-vitro in primary cultured human KCs. RESULTS: We found the expression of IARS was higher in psoriatic skin than in healthy controls. In IMQ-induced psoriasis-like C57BL/6 J mouse model, MUP reversed IMQ-induced keratinocytes proliferation, expression of inflammatory cytokines and infiltration of immune cells. Furthermore, in cultured human keratinocytes, MUP inhibited proliferation, but promoted apoptosis, which may be related with STAT3 signaling pathway. CONCLUSION: Our finding of blocking the infiltration of immune cells by inhibiting the formation of IARS, could be one mechanism to explain the effect of MUP in the treatment of psoriasis. Developing strategies targeting suppression IARS should open new perspectives for the treatment of psoriasis. Video Abstract.

Gradually increasing the dosing interval of Secukinumab for moderate to severe plaque psoriasis: A single-center, uncontrolled, prospective study in 36 weeks.

Secukinumab is a recombinant, fully human monoclonal anti-IL-17A antibody approved to treat moderate-to-severe psoriasis and psoriatic arthritis. Its effectiveness and safety have been confirmed, but a gradual increase in the secukinumab dosing interval has not been investigated. To assess the feasibility, efficacy, and safety of gradually increasing the secukinumab dosing interval; the interval duration was determined by changes in the Psoriasis Area and Severity Index scores. Patients with moderate-to-severe plaque psoriasis received secukinumab 300 mg subcutaneously at baseline and weeks 0, 1, 2, and 3. At week 4, the improvement from baseline PASI guided the next injection time until week 36. In total, 83 patients were recruited. PASI 75 was achieved by 80%, 96%, and 95% of patients at weeks 4, 12, and 36, respectively. PASI 90 was achieved by 54%, 95%, and 84% of patients at weeks 4, 12, and 36, respectively. PASI 100 was achieved by 28%, 89%, and 68% of patients at weeks 4, 12, and 36, respectively. The average PASI score (1.05 ± 1.83) was significantly lower at week 36 than at baseline. Most patients reached PASI 75 at week 36 in our modified study. This study may provide information for future biotherapies.

Tofacitinib for the treatment of erythematotelangiectatic and papulopustular rosacea: A retrospective case series.

Rosacea is a chronic inflammatory skin disease characterized by facial erythema, papules, pustules, telangiectasia, and flushing. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway appears to play a role in the pathogenesis of rosacea. Our study preliminarily explored the efficacy of JAK inhibitor tofacitinib in the treatment of rosacea. We retrospectively reviewed the cases of 21 patients with rosacea who were treated with oral tofacitinib. Patients received oral tofacitinib 5 mg as either monotherapy or adjunctive therapy. We have observed that 15 out of 21 patients (71.4%) patients experienced significant regression of erythema on the face (IGA ≤ 1), and a mean change of -2.24 in the Investigator's Global Assessment (IGA) score was significant improvement from baseline. Treatment with oral tofacitinib might be a potentially effective treatment to ameliorate the symptoms of rosacea.

Comparison of Long-Term Effectiveness and Safety of Microwave and Surgery in the Treatment of Axillary Osmidrosis: A Single-Center Retrospective Study.

BACKGROUND: A microwave-based device is a newly developed method for treating axillary osmidrosis. Few studies have compared the difference between microwave therapy and subcutaneous curettage for axillary osmidrosis. OBJECTIVE: To compare the long-term effectiveness, complications, and recurrence of osmidrosis after microwave therapy and subcutaneous curettage. METHODS AND MATERIALS: Medical records of 155 patients with osmidrosis treated with microwave therapy or subcutaneous curettage were reviewed retrospectively. Demographic data, visual analog scale for odor, hyperhidrosis disease scale, complications, and recurrence were analyzed. RESULTS: Osmidrosis improved significantly in both treatment groups at 6 months. Effective improvement was observed in 90% and 23% of the patients in the surgery and microwave groups, respectively, after 3 years postoperatively. The recurrence rates were 39% and 21% in the microwave and surgery groups, respectively. The transient complication rate was higher in the microwave group, and long-term complications only occurred in the surgery group. CONCLUSION: Subcutaneous curettage is a more effective approach for axillary osmidrosis. However, microwave therapy is recommended for patients with cosmetic concerns.

Increased CCL24 and CXCL7 levels in the cerebrospinal fluid of patients with neurosyphilis.

BACKGROUND: Monocytes are recruited into the cerebrospinal fluid (CSF) of patients with neurosyphilis, suggesting abnormal chemokine expression. We aimed to investigate the aberrant expression of chemokines in the CSF of these patients. METHODS: CSF and serum samples were collected from patients with neurosyphilis between July 2017 and June 2019 in the Dermatology Department, Second Affiliated Hospital of Zhejiang University. Differences in the expression of 38 chemokines between patients with and without neurosyphilis were detected using RayBio® Human Chemokine Antibody Array C1. CCL24 and CXCL7 levels in the patients' CSF and serum were further measured using RayBio® CCL24 and CXCL7 ELISA kits. RESULTS: Ninety-three CSF and serum samples of patients with syphilis were collected. Antibody array analysis showed that the CSF levels of CCL24 (P = .0185), CXCL7 (P < .0001), CXCL13 (P < .0001), CXCL10 (P < .0001), and CXCL8 (P < .0001) were significantly higher in patients with than without neurosyphilis. ELISA confirmed significantly higher CCL24 and CXCL7 levels in the CSF of patients with than without neurosyphilis (CCL24: 6.082 ± 1.137 pg/mL vs 1.773 ± 0.4565 pg/mL, P = .0037; CXCL7: 664.3 ± 73.19 pg/mL vs 431.1 ± 90.54 pg/mL, P = .0118). Increased CCL24 and CXCL7 expression was seen throughout all neurosyphilis stages, had moderate diagnostic efficiency for neurosyphilis, and correlated poorly with CSF cell count and Venereal Disease Research Laboratory titer. CSF CCL24 levels also correlated poorly with CSF protein concentration. CONCLUSION: Abnormally high CSF chemokines levels may play a role in the pathogenesis of neurosyphilis.

Exosomal microRNA profiles from serum and cerebrospinal fluid in neurosyphilis.

OBJECTIVE: Changes in microRNAs (miRNAs) in the cerebrospinal fluid (CSF) are associated with different neurological diseases. Since alternations of miRNAs in neurosyphilis are insufficiently investigated, we analysed miRNAs in the CSF of patients suffering from neurosyphilis. METHODS: Exosomes were isolated from serum and CSF. Levels of 44 miRNAs were determined using quantitative real-time PCR-based miRNA array. RESULTS: In patients with neurosyphilis (NSP), miR-590-5p, miR-570-3p and miR-570-5p were upregulated in the CSF and serum, when compared with patients with syphilis without neurosyphilis (SP). miR-590-5p and miR-570-3p were significantly upregulated (p<0.001). The expression of miR-21-5p was upregulated only in the CSF of NSP. Significant downregulation was observed for miR-93-3p in the CSF and serum of NSP. No statistical difference was found in the expression of miR-7-5p, miR-1307-5p, miR-203a-3p, miR-16, miR-23b-3p and miR-27b-5p in the CSF and serum of NSP and SP. CONCLUSION: For the first time, regulation profiles in miRNA in the CSF and serum were analysed in NSP. We found significant differences in upregulation and downregulation. Therefore, miRNAs may be potential biomarkers for the presence of neurosyphilis.

Decrease of galectin-3 in keratinocytes: A potential diagnostic marker and a critical contributor to the pathogenesis of psoriasis.

Psoriasis-specific proteins dysregulated in keratinocytes and involved in the pathophysiological process of psoriasis remains elusive. We report here that epidermal galectin-3 expression is significantly downregulated in lesional skin, but not in non-lesional skin in psoriasis patients, nor in a group of diseases known as psoriasiform dermatitis clinically and histologically similar to psoriasis. The deficiency of epidermal galectin-3 is sufficient to promote development of psoriatic lesions, as evidenced by more severe skin inflammation in galectin-3 knockout (gal3-/-) mice, compared to wild-type mice, after imiquimod treatment, and in skin from gal3-/- mice grafted onto wildtype mice. The development of psoriatic-like lesions is attributable to 1) the spontaneously tuning up of psoriasis signatures in keratinocytes through JNK pathway; and 2) neutrophil accumulation caused by the enhanced leukocyte-recruiting capacity associated with overexpression of S100A7-9 and CXCL-1, 8 in keratinocytes with impaired galectin-3 expression. Psoriasis-like skin inflammation is significantly improved in gal-3-/- mice both by inhibition of neutrophils accumulation with a selective CXCR2 antagonist of SB225002, and by intracutaneous injection of recombinant galectin-3. Overall, these findings offer promising galectin-3-related diagnostic and therapeutic resolutions of psoriasis.

Impaired nuclear translocation of glucocorticoid receptors: novel findings from psoriatic epidermal keratinocytes.

Psoriasis is a chronic proliferative skin disease and is usually treated with topical glucocorticoids, which act through the glucocorticoid receptor (GR), a component of the physiological systems essential for immune responses, differentiation, and homeostasis. To investigate the possible role of GR in the pathogenesis of psoriasis, normal and psoriatic lesional skin were recruited. Firstly, the immunolocalization of GR in the skin and cultured epidermal keratinocytes were determined by immunofluorescence. In normal skin and cultured human epidermal keratinocytes, intracellular GR is localized in the nuclei, while in psoriatic skin and cultured keratinocytes, GR is in the cytoplasm. Next, we investigated possible factors associated with the cytoplasmic distribution. We found that VEGF and IFN-γ led to impaired nuclear translocation of GR through p53 and microtubule-inhibitor, vincristine, and inhibited nuclear uptake of GR in normal keratinocytes. In addition to dexamethasone, interleukin (IL)-13 was also able to transfer GR into nuclei of psoriatic keratinocytes. Furthermore, discontinuation of dexamethasone induced cytoplasmic retention of GR in normal keratinocytes. In contrast, energy depletion of normal epidermal keratinocytes did not change the nuclear distribution of GR. To confirm our findings in vivo, an imiquimod-induced psoriasis-like skin mouse model was included. IL-13 ameliorated (but vincristine exacerbated) the skin lesions on the mouse. Taken together, our findings define that impaired nuclear translocation of GR is associated with VEGF, IFN-γ, p53, and microtubule. Therapeutic strategies designed to accumulate GR in the nucleus, such as IL-13, may be beneficial for the therapy of psoriasis.

Clinical and laboratory features of neurosyphilis: A single-center, retrospective study of 402 patients.

Neurosyphilis is a serious global health issue and a big challenge in developing countries, related risk factors should be taken seriously. Although there are a certain number of studies describing the clinical and laboratory features and risk factors for symptomatic neurosyphilis (SNS), but some risk factors are still controversial. The aim of this research is to investigate the association between asymptomatic neurosyphilis (ANS) and symptomatic neurosyphilis (SNS) and identify risk factors for SNS. This was a single-center retrospective study in a tertiary hospital in Hangzhou, China. The clinical and laboratory features of neurosyphilis patients from January 1, 2011 to July 31, 2020 were retrospectively reviewed. After detailed assessments based on diagnostic criteria, 402 patients with neurosyphilis were enrolled in this study. There were 299 male and 103 female patients. The median age was 53.5 (45, 61) years. Multivariable logistic regression displayed that SNS were correlated with the following factors: male, without anti-syphilis treatment, high pretreatment serum RPR titer and positive CSF RPR. Our findings suggest a potential association between SNS and specific factors, including male gender, elevated pretreatment serum and CSF RPR titers. Moreover, our observations indicate that individuals without anti-syphilis treatment may be at a higher likelihood of manifesting the symptomatic form. This underscores the importance of considering gender, RPR titers, and treatment status as significant contributors to the risk profile for SNS.

Biologics protect psoriasis patients from being exacerbated by COVID-19 infection.

Background: Patients with psoriasis may experience an exacerbation in symptoms following COVID-19 infection. After abandoning 'zero COVID' strategies, China experienced a surge of Omicron infections. Objectives: We aimed to investigate psoriasis exacerbation in psoriatic patients with COVID-19, following treatment with three different biologics, adalimumab, secukinumab, and ixekizumab. Methods: We performed a prospective study (n = 209) at our hospital between November 01, 2022, and February 15, 2023. We defined △ PASI as post-COVID-19 PASI minus pre-COVID-19 PASI. Two endpoints were set in this study. △ PASI >0 was defined as exacerbation of psoriasis after infection. △ PASI >3 was defined as a severe exacerbation of psoriasis symptoms after infection. In addition, serum OAS1, OAS2, and OAS3 were also assessed. Results: Results showed that the severity of psoriasis can worsen after COVID-19 infection, and a smaller proportion of patients taking biologics developed worsening psoriasis compared to those not using biologics; however, only the patients taking ixekizumab demonstrated a statistically significant difference (p < 0.05), while those taking adalimumab or secukinumab didn't. What's more, the use of biological agents suppressed the serum OAS2 and OAS3 at low levels and elevated the serum OAS1 level in patients with psoriasis. Conclusions: This study provided new insights into the protective role of biological agents in patients with psoriasis who were infected with COVID-19, and we proposed that psoriatic patients treated with biologics should continue with the treatment during the COVID-19 pandemic.

Glycyl-tRNA Synthetase Induces Psoriasis-Like Skin by Facilitating Skin Inflammation and Vascular Endothelial Cell Angiogenesis.

Psoriasis is characterized by excessive keratinocyte proliferation and immunocyte infiltration, but the underlying pathogenesis remains unclear. Aminoacyl-tRNA synthetases are universally expressed enzymes that catalyze the first step of protein synthesis. Glycyl-tRNA synthetase (GARS) is a member of the aminoacyl-tRNA synthetase family. In addition to its canonical function, we found that GARS was overexpressed in the serum and skin lesions of patients with psoriasis. Moreover, GARS was highly expressed in human skin keratinocytes, and GARS knockdown in keratinocytes suppressed cell proliferation and promoted apoptosis through NF-κB/MAPK signaling pathway. Moreover, intradermal injection of recombinant GARS protein caused skin thickening, angiogenesis, and IFN/TNF-driven skin inflammation. Intriguingly, the reported functional receptor for GARS, cadherin 6 (CDH6), was specifically expressed in vascular endothelial cells, and we found that keratinocyte-derived GARS promotes inflammation and angiogenesis of vascular endothelial cells through CDH6. In addition, intradermal injection of GARS aggravated the phenotype and angiogenesis in imiquimod-induced psoriasiform dermatitis models, whereas the psoriatic phenotype and angiogenesis were relieved after knockdown of GARS by adeno-associated virus. Taken together, the results of this study identify the critical role of GARS in the pathogenesis of psoriasis and suggest that blocking GARS may be a therapeutic approach for alleviating psoriasis.