Activation of Human CD8+ T Cells with Nitroso Dapsone-Modified HLA-B*13:01-Binding Peptides.

Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of the antigenic determinants that interact with HLA and whether T cell stimulatory peptides contain the bound drug metabolite has not been defined. Because susceptibility to dapsone hypersensitivity is associated with the expression of HLA-B*13:01, we have designed and synthesized nitroso dapsone-modified, HLA-B*13:01 binding peptides and explored their immunogenicity using T cells from hypersensitive human patients. Cysteine-containing 9-mer peptides with high binding affinity to HLA-B*13:01 were designed (AQDCEAAAL [Pep1], AQDACEAAL [Pep2], and AQDAEACAL [Pep3]), and the cysteine residue was modified with nitroso dapsone. CD8+ T cell clones were generated and characterized in terms of phenotype, function, and cross-reactivity. Autologous APCs and C1R cells expressing HLA-B*13:01 were used to determine HLA restriction. Mass spectrometry confirmed that nitroso dapsone-peptides were modified at the appropriate site and were free of soluble dapsone and nitroso dapsone. APC HLA-B*13:01-restricted nitroso dapsone-modified Pep1- (n = 124) and Pep3-responsive (n = 48) CD8+ clones were generated. Clones proliferated and secreted effector molecules with graded concentrations of nitroso dapsone-modified Pep1 or Pep3. They also displayed reactivity against soluble nitroso dapsone, which forms adducts in situ, but not with the unmodified peptide or dapsone. Cross-reactivity was observed between nitroso dapsone-modified peptides with cysteine residues in different positions in the peptide sequence. These data characterize a drug metabolite hapten CD8+ T cell response in an HLA risk allele-restricted form of drug hypersensitivity and provide a framework for structural analysis of hapten HLA binding interactions.

The molecular basis of dapsone activation of CYP2C9-catalyzed nonsteroidal anti-inflammatory drug oxidation.

Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of nonsteroidal anti-inflammatory drugs in vitro. Here, we conducted molecular dynamics simulations (MDS) together with enzyme kinetic investigations and site-directed mutagenesis to elucidate the molecular basis of the activation of CYP2C9-catalyzed S-flurbiprofen 4'-hydroxylation and S-naproxen O-demethylation by dapsone. Supplementation of incubations of recombinant CYP2C9 with dapsone increased the catalytic efficiency of flurbiprofen and naproxen oxidation by 2.3- and 16.5-fold, respectively. MDS demonstrated that activation arises predominantly from aromatic interactions between the substrate, dapsone, and the phenyl rings of Phe114 and Phe476 within a common binding domain of the CYP2C9 active site, rather than involvement of a distinct effector site. Mutagenesis of Phe114 and Phe476 abrogated flurbiprofen and naproxen oxidation, and MDS and kinetic studies with the CYP2C9 mutants further identified a pivotal role of Phe476 in dapsone activation. MDS additionally showed that aromatic stacking interactions between two molecules of naproxen are necessary for binding in a catalytically favorable orientation. In contrast to flurbiprofen and naproxen, dapsone did not activate the 4'-hydroxylation of diclofenac, suggesting that the CYP2C9 active site favors cooperative binding of nonsteroidal anti-inflammatory drugs with a planar or near-planar geometry. More generally, the work confirms the utility of MDS for investigating ligand binding in CYP enzymes.

Dapsone for paediatric chronic immune thrombocytopenia: Short report from a tertiary centre in South India.

Immune thrombocytopenia (ITP) resolves in most children within 3-12 months of diagnosis. Chronic ITP affects 10%-20% of patients, some of whom require treatment. Several second-line agents are efficacious in this group of patients. This paper describes our experience of using dapsone as a single second-line agent in children with chronic ITP. One hundred and three children with chronic ITP were seen at our centre from January 2012 to December 2016. Forty-five children met the inclusion criteria and received dapsone; 17 (37.8%) were boys; and 28 (62.2%) were girls. Early response to dapsone was seen in 37.8% of patients. The median duration of long-term follow-up was 50 months, and at least a partial response was seen in 64.4% of the patients. Dapsone offers good initial response rates and sustained remission in paediatric chronic ITP, comparable to other therapeutic agents available.

Clinical Features of Paediatric Inflammatory Epidermolysis Bullosa Acquisita: A Case Series Study.

Epidermolysis bullosa acquisita (EBA) rarely develops in childhood. This study retrospectively recruited paediatric patients with EBA (age ≤ 16 years), diagnosed by clinical and histopathological features and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assay (ELISA), and reviews their clinical manifestations, histopathology, immunological features, and responses to various treatments. All 7 included patients presented with inflammatory EBA. Among them, 3 had a bullous pemphigoid-like phenotype. Pathologically, in addition to dermal-epidermal blistering, in all patients, the distribution of neutrophils was superficial perivascular or interstitial, or in the dermal papilla. Mixed neutrophils and eosinophils were detected in 2 of the 3 patients with bullous pemphigoid-like phenotypes. In addition to treatment with glucocorticoids, dapsone was administered in 4 patients, while thalidomide and sulfasalazine were administered in 1 patient. All patients responded to the these therapies. Relapse was mainly due to reduction and cessation of glucocorticoids. In conclusion, EBA in childhood may be unique, and thus distinct from its adult counterpart. Specific treatment and follow-up protocols are required for therapy of this rare autoimmune skin disease in children.

An Open-label Study to Investigate the Efficacy and Tolerability of Dapsone Gel, 7.5% in the Treatment of Acne Vulgaris in Men and Women With Skin of Color

INTRODUCTION: Acne vulgaris is a common skin disease prevalent in skin of color patients. Studies have demonstrated that dapsone gel, 7.5% (Aczone) used once daily is effective, safe, and well-tolerated for the treatment of acne in both men and women. However, minimal data are available in skin of color populations. This single-center, open-label clinical study investigated the efficacy and safety of dapsone gel, 7.5% in the treatment of moderate to severe acne vulgaris in patients with Fitzpatrick skin types IV-VI. METHODS: Twenty (20) adult subjects with moderate to severe acne and Fitzpatrick skin types IV-VI were enrolled in this study and treated with dapsone gel, 7.5% once daily for 24 weeks. RESULTS: Dapsone gel, 7.5% applied daily for 24 weeks reduced acne severity, post-inflammatory hyperpigmentation, and decreased new inflammatory and noninflammatory acne lesions in skin of color patients with moderate to severe acne vulgaris. Treatment resulted in improved acne health-related quality of life and patient symptoms related to acne, including patient-reported post-inflammatory hyperpigmentation, especially with a treatment duration of 18 weeks or longer.  Limitations: The sample size was small and underpowered to detect statistically significant changes in some endpoints. CONCLUSION: Dapsone gel 7.5% was safe, well-tolerated, and efficacious in treating acne vulgaris and post-inflammatory hyperpigmentation in skin-of-color patients. Larger studies involving skin-of-color populations with acne vulgaris are warranted. J Drugs Dermatol. 2024;23(6):410-417. doi:10.36849/JDD.7897.

Experimental and Theoretical Insights into the Intermolecular Interactions in Saturated Systems of Dapsone in Conventional and Deep Eutectic Solvents.

Solubility is not only a crucial physicochemical property for laboratory practice but also provides valuable insight into the mechanism of saturated system organization, as a measure of the interplay between various intermolecular interactions. The importance of these data cannot be overstated, particularly when dealing with active pharmaceutical ingredients (APIs), such as dapsone. It is a commonly used anti-inflammatory and antimicrobial agent. However, its low solubility hampers its efficient applications. In this project, deep eutectic solvents (DESs) were used as solubilizing agents for dapsone as an alternative to traditional solvents. DESs were composed of choline chloride and one of six polyols. Additionally, water-DES mixtures were studied as a type of ternary solvents. The solubility of dapsone in these systems was determined spectrophotometrically. This study also analyzed the intermolecular interactions, not only in the studied eutectic systems, but also in a wide range of systems found in the literature, determined using the COSMO-RS framework. The intermolecular interactions were quantified as affinity values, which correspond to the Gibbs free energy of pair formation of dapsone molecules with constituents of regular solvents and choline chloride-based deep eutectic solvents. The patterns of solute-solute, solute-solvent, and solvent-solvent interactions that affect solubility were recognized using Orange data mining software (version 3.36.2). Finally, the computed affinity values were used to provide useful descriptors for machine learning purposes. The impact of intermolecular interactions on dapsone solubility in neat solvents, binary organic solvent mixtures, and deep eutectic solvents was analyzed and highlighted, underscoring the crucial role of dapsone self-association and providing valuable insights into complex solubility phenomena. Also the importance of solvent-solvent diversity was highlighted as a factor determining dapsone solubility. The Non-Linear Support Vector Regression (NuSVR) model, in conjunction with unique molecular descriptors, revealed exceptional predictive accuracy. Overall, this study underscores the potency of computed molecular characteristics and machine learning models in unraveling complex molecular interactions, thereby advancing our understanding of solubility phenomena within the scientific community.

Developmental changes in retention and generalization of nonadjacent dependencies over a period containing sleep in 18-mo-old infants.

Sleep promotes the stabilization of memories in adulthood, with a growing literature on the benefits of sleep for memory in infants and children. In two studies, we examined the role of sleep in the retention and generalization of nonadjacent dependencies (NADs; e.g., a-X-b/c-X-d phrases) in an artificial language. Previously, a study demonstrated that over a delay of 4 h, 15 mo olds who nap after training retain a general memory of the NAD rule instead of memory for specific NADs heard during training. In experiment 1, we designed a replication of the nap condition used in the earlier study but tested 18-mo-old infants. Infants of this age retained veridical memory for specific NADs over a delay containing sleep, providing preliminary evidence of the development of memory processes (experiment 1). In experiment 2, we tested 18 mo olds' ability to generalize the NAD to new vocabulary, finding only infants who napped after training generalized their knowledge of the pattern to completely novel phrases. Overall, by 18 mo of age, children retain specific memories over a period containing sleep, and sleep promotes abstract memories to a greater extent than wakefulness.

Non-biologic immunosuppressive drugs for inflammatory and autoimmune skin diseases.

Non-biologic immunosuppressive drugs, such as azathioprine, dapsone or methotrexate are fundamental treatment options for a wide range of autoimmune and chronic inflammatory skin diseases. Some of these drugs were initially used for malignancies (e.g., azathioprine or methotrexate) or infectious diseases (e.g., hydroxychloroquine or dapsone) but are nowadays mostly used for their immunosuppressive/immunomodulating action. Although dermatologists have years of clinical experience with these drugs, some of the mechanisms of action are not fully understood and are the subject of research. Although these drugs are commonly used, lack of experience or knowledge regarding their safety profiles and management leads to skepticism among physicians. Here, we summarize the mechanism of action and detailed management of adverse effects of the most commonly used immunosuppressive drugs for skin diseases. Furthermore, we discuss the management of these drugs during pregnancy and breastfeeding, as well as their interaction and handling during vaccination.

Solubility of dapsone in deep eutectic solvents: Experimental analysis, molecular insights and machine learning predictions.

BACKGROUND: Dapsone (DAP) is an anti-inflammatory and antimicrobial active pharmaceutical ingredient used to treat, e.g., AIDS-related diseases. However, low solubility is a feature hampering its efficient use. OBJECTIVES: First, deep eutectic solvents (DES) were used as solubilizing agents for DAP as an alternative to traditional solvents. Second, intermolecular interactions in the systems were described and quantified. Finally, the solubility prediction model, previously created using the machine learning protocol, was extended and improved using new data obtained for eutectic systems. MATERIAL AND METHODS: New DES were created by blending choline chloride (ChCl) with 6 selected polyols. The solubility of DAP in these solvents was measured spectrophotometrically. The impact of water dilution on the solubility curve was investigated. Experimental research was enriched with theoretical interpretations of intermolecular interactions, identifying the most probable pairs in the systems. Dapsone self-association and its ability to interact with components of the analyzed systems were considered. Thermodynamic characteristics of pairs were utilized as molecular descriptors in the machine learning process, predicting solubility in both traditional organic solvents and the newly designed DES. RESULTS: The newly formulated solvents demonstrated significantly higher efficiency compared to traditional organic solvents, and a small addition of water increased solubility, indicating its role as a co-solvent. The interpretation of the mechanism of DAP solubility highlighted the competitive nature of self-association and pair formation. Thermodynamic parameters characterizing affinity were instrumental in developing an efficient model for theoretical screening across diverse solvent classes. The study emphasized the necessity of retraining models when introducing new experimental data, as exemplified by enriching the model with data from DES. CONCLUSIONS: The research showcased the efficacy of developing new DES for enhancing solubility and creating environmentally and pharmaceutically viable systems, using DAP as an example. Molecular interactions proved valuable in understanding solubility mechanisms and formulating predictive models through machine learning processes.

Hemolysis and Metabolic Lesion of G6PD Deficient RBCs in Response to Dapsone Hydroxylamine in a Humanized Mouse Model.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans (∼5% of all individuals). G6PD deficiency (G6PDd) is caused by an unstable enzyme and manifests most strongly in red blood cells (RBCs) that cannot synthesize new protein. G6PDd RBCs have decreased ability to mitigate oxidative stress due to lower levels of NADPH, as a result of a defective pentose phosphate pathway. Accordingly, oxidative drugs can result in hemolysis and potentially life-threatening anemia in G6PDd patients. Dapsone is a highly useful drug for treating a variety of pathologies but oral dapsone is contraindicated in patients with G6PDd due to oxidative stress-induced anemia. Dapsone must be metabolized to become hemolytic. Dapsone hydroxylamine (DDS-NOH) has been implicated as the major hemolytic dapsone metabolite, but this has never been tested on G6PDd RBCs with in vivo circulation as a metric. Moreover, the metabolic lesion caused by DDS-NOH is unknown. We report that RBCs from a novel humanized mouse expressing the human Mediterranean G6PD-deficient variant have increased sensitivity to DDS-NOH. In addition, we show that DDS-NOH damaged RBCs can either undergo sequestration (with subsequent return to circulation) or permanent removal in a dose-dependent manner, with G6PD-sufficient RBCs mostly being sequestered, and G6PDd RBCs mostly being permanently removed. Finally, we characterize the metabolic lesion caused by DDS-NOH in G6PDd RBCs and report a blockage in terminal glycolysis resulting in a cellular accumulation of pyruvate. These findings confirm DDS-NOH as a hemolytic metabolite and elucidate metabolic effects of DDS-NOH on G6PDd RBCs. SIGNIFICANCE STATEMENT: These findings confirm that dapsone hydroxylamine, an active metabolite of dapsone, causes in vivo clearance of murine red blood cells expressing a human variant of deficient glucose 6-phosphate dehydrogenase (G6PD), an enzymopathy that affects half a billion individuals (G6PD deficiency). Both cellular mechanisms of clearance (sequestration versus destruction) and specific metabolic disturbances caused by dapsone hydroxylamine are elucidated, providing novel mechanistic understanding.

Detection of Hepatic Drug Metabolite-Specific T-Cell Responses Using a Human Hepatocyte, Immune Cell Coculture System.

Drug-responsive T-cells are activated with the parent compound or metabolites, often via different pathways (pharmacological interaction and hapten). An obstacle to the investigation of drug hypersensitivity is the scarcity of reactive metabolites for functional studies and the absence of coculture systems to generate metabolites in situ. Thus, the aim of this study was to utilize dapsone metabolite-responsive T-cells from hypersensitive patients, alongside primary human hepatocytes to drive metabolite formation, and subsequent drug-specific T-cell responses. Nitroso dapsone-responsive T-cell clones were generated from hypersensitive patients and characterized in terms of cross-reactivity and pathways of T-cell activation. Primary human hepatocytes, antigen-presenting cells, and T-cell cocultures were established in various formats with the liver and immune cells separated to avoid cell contact. Cultures were exposed to dapsone, and metabolite formation and T-cell activation were measured by LC-MS and proliferation assessment, respectively. Nitroso dapsone-responsive CD4+ T-cell clones from hypersensitive patients were found to proliferate and secrete cytokines in a dose-dependent manner when exposed to the drug metabolite. Clones were activated with nitroso dapsone-pulsed antigen-presenting cells, while fixation of antigen-presenting cells or omission of antigen-presenting cells from the assay abrogated the nitroso dapsone-specific T-cell response. Importantly, clones displayed no cross-reactivity with the parent drug. Nitroso dapsone glutathione conjugates were detected in the supernatant of hepatocyte immune cell cocultures, indicating that hepatocyte-derived metabolites are formed and transferred to the immune cell compartment. Similarly, nitroso dapsone-responsive clones were stimulated to proliferate with dapsone, when hepatocytes were added to the coculture system. Collectively, our study demonstrates the use of hepatocyte immune cell coculture systems to detect in situ metabolite formation and metabolite-specific T-cell responses. Similar systems should be used in future diagnostic and predictive assays to detect metabolite-specific T-cell responses when synthetic metabolites are not available.

Non-compartmental and population pharmacokinetic analysis of dapsone in healthy NIGERIANS: A pilot study.

Dapsone is employed for both non-dermatological and dermatological indications but with non-existent population pharmacokinetics (popPK) data in Nigerians. This study was therefore designed to develop a popPK model in Nigerians. Non-compartmental analysis and nonlinear mixed effects modelling were utilized for data analysis. Eleven participants administered 50 mg dapsone tablet were included in the analysis. Derived pharmacokinetic parameters were: Cmax = 1.16 ± 0.32 µg/mL, Tmax = 3.77 ± 2.40 h, and t1/2z = 30.23 ± 11.76 h. PopPK model parameter estimates with inter-individual variability were Tlag = 0.40 h (10.0%, fixed); ka = 1.78 h-1 (75.9%); V/F = 89.25 L (21.6%); and Cl/F = 1.32 Lh-1 (27.7%). Sex was significantly associated with Cl/F, and body weight with V/F. Best popPK model was one-compartment with lag time, and first-order absorption and elimination. Sex and body weight significantly influenced the clearance and distribution volume of dapsone respectively.

Overview and Current Advances in Dapsone Hypersensitivity Syndrome.

PURPOSE OF REVIEW: As a sulfone antibacterial agent, dapsone has been widely used to treat leprosy. Moreover, dapsone is also used in many immune diseases such as herpetic dermatitis because of its anti-inflammatory and immunomodulatory effects. However, dapsone can cause several adverse effects, the most serious being dapsone hypersensitivity syndrome. Dapsone hypersensitivity syndrome is characterized by a triad of eruptions, fever, and organ involvement, which limits the application of dapsone to some extent. RECENT FINDINGS: In this article, we review current research about the interaction model between HLA-B*13:01, dapsone, and specific TCR in dapsone-induced drug hypersensitivity. In addition to the proposed mechanisms, we also discussed clinical features, treatment progress, prevalence, and prevention of dapsone hypersensitivity syndrome. These studies reveal the pathogenesis, clinical features, and prevalence from the perspectives of genetic susceptibility and innate and adaptive immunity in dapsone hypersensitivity syndrome, thereby guiding clinicians on how to diagnose, prevent, and treat dapsone hypersensitivity syndrome.

Interventions for bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. Oral steroids are the standard treatment. We have updated this review, which was first published in 2002, because several new treatments have since been tried. OBJECTIVES: To assess the effects of treatments for bullous pemphigoid. SEARCH METHODS: We updated searches of the following databases to November 2021: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched five trial databases to January 2022, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: RCTs of treatments for immunofluorescence-confirmed bullous pemphigoid. DATA COLLECTION AND ANALYSIS: At least two review authors, working independently, evaluated the studies against the review's inclusion criteria and extracted data from included studies. Using GRADE methodology, we assessed the certainty of the evidence for each outcome in each comparison. Our primary outcomes were healing of skin lesions and mortality. MAIN RESULTS: We identified 14 RCTs (1442 participants). The main treatment modalities assessed were oral steroids, topical steroids, and the oral anti-inflammatory antibiotic doxycycline. Most studies reported mortality but adverse events and quality of life were not well reported. We decided to look at the primary outcomes 'disease control' and 'mortality'. Almost all studies investigated different comparisons; two studies were placebo-controlled. The results are therefore based on a single study for each comparison except azathioprine. Most studies involved only small numbers of participants. We assessed the risk of bias for all key outcomes as having 'some concerns' or high risk, due to missing data, inappropriate analysis, or insufficient information. Clobetasol propionate cream versus oral prednisone Compared to oral prednisone, clobetasol propionate cream applied over the whole body probably increases skin healing at day 21 (risk ratio (RR 1.08, 95% confidence interval (CI) 1.03 to 1.13; 1 study, 341 participants; moderate-certainty evidence). Skin healing at 21 days was seen in 99.8% of participants assigned to clobetasol and 92.4% of participants assigned to prednisone. Clobetasol propionate cream applied over the whole body compared to oral prednisone may reduce mortality at one year (RR 0.73, 95% CI 0.53 to 1.01; 1 study, 341 participants; low-certainty evidence). Death occurred in 26.5% (45/170) of participants assigned to clobetasol and 36.3% (62/171) of participants assigned to oral prednisone. This study did not measure quality of life. Clobetasol propionate cream may reduce risk of severe complications by day 21 compared with oral prednisone (RR 0.65, 95% CI 0.50 to 0.86; 1 study, 341 participants; low-certainty evidence). Mild clobetasol propionate cream regimen (10 to 30 g/day) versus standard clobetasol propionate cream regimen (40 g/day) A mild regimen of topical clobetasol propionate applied over the whole body compared to the standard regimen probably does not change skin healing at day 21 (RR 1.00, 95% CI 0.97 to 1.03; 1 study, 312 participants; moderate-certainty evidence). Both groups showed complete healing of lesions at day 21 in 98% participants. A mild regimen of topical clobetasol propionate applied over the whole body compared to the standard regimen may not change mortality at one year (RR 1.00, 95% CI 0.75 to 1.32; 1 study, 312 participants; low-certainty evidence), which occurred in 118/312 (37.9%) participants. This study did not measure quality of life. A mild regimen of topical clobetasol propionate applied over the whole body compared to the standard regimen may not change adverse events at one year (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 309 participants; low-certainty evidence). Doxycycline versus prednisolone Compared to prednisolone (0.5 mg/kg/day), doxycycline (200 mg/day) induces less skin healing at six weeks (RR 0.81, 95% CI 0.72 to 0.92; 1 study, 213 participants; high-certainty evidence). Complete skin healing was reported in 73.8% of participants assigned to doxycycline and 91.1% assigned to prednisolone. Doxycycline compared to prednisolone probably decreases mortality at one year (RR 0.25, 95% CI 0.07 to 0.89; number needed to treat for an additional beneficial outcome (NNTB) = 14; 1 study, 234 participants; moderate-certainty evidence). Mortality occurred in 2.4% (3/132) of participants with doxycycline and 9.7% (11/121) with prednisolone. Compared to prednisolone, doxycycline improved quality of life at one year (mean difference 1.8 points lower, which is more favourable on the Dermatology Life Quality Index, 95% CI 1.02 to 2.58 lower; 1 study, 234 participants; high-certainty evidence). Doxycycline compared to prednisolone probably reduces severe or life-threatening treatment-related adverse events at one year (RR 0.59, 95% CI 0.35 to 0.99; 1 study, 234 participants; moderate-certainty evidence). Prednisone plus azathioprine versus prednisone It is unclear whether azathioprine plus prednisone compared to prednisone alone affects skin healing or mortality because there was only very low-certainty evidence from two trials (98 participants). These studies did not measure quality of life. Adverse events were reported in a total of 20/48 (42%) participants assigned to azathioprine plus prednisone and 15/44 (34%) participants assigned to prednisone. Nicotinamide plus tetracycline versus prednisone It is unclear whether nicotinamide plus tetracycline compared to prednisone affects skin healing or mortality because there was only very low-certainty evidence from one trial (18 participants). This study did not measure quality of life. Fewer adverse events were reported in the nicotinamide group. Methylprednisolone plus azathioprine versus methylprednisolone plus dapsone It is unclear whether azathioprine plus methylprednisolone compared to dapsone plus methylprednisolone affects skin healing or mortality because there was only very low-certainty evidence from one trial (54 participants). This study did not measure quality of life. A total of 18 adverse events were reported in the azathioprine group and 13 in the dapsone group. AUTHORS' CONCLUSIONS: Clobetasol propionate cream applied over the whole body is probably similarly effective as, and may cause less mortality than, oral prednisone for treating bullous pemphigoid. Lower-dose clobetasol propionate cream applied over the whole body is probably similarly effective as standard-dose clobetasol propionate cream and has similar mortality. Doxycycline is less effective but causes less mortality than prednisolone for treating bullous pemphigoid. Other treatments need further investigation.

Dapsone to Treat Moderate-to-Severe Hidradenitis Suppurativa: A Retrospective Case-Series.

BACKGROUND: Management of hidradenitis suppurativa (HS) is challenging since no single treatment provides consistently effective results, leaving patients with frequent relapses. Dapsone combines anti-microbial and anti-inflammatory properties that address aspects of HS pathogenesis. Few studies have evaluated the efficacy of oral dapsone on HS, especially in severe disease. OBJECTIVE: This study aims to evaluate the clinical outcomes of patients with moderate-to-severe HS treated with dapsone. METHODS: This retrospective chart review evaluated HS patients treated with oral dapsone over the past 10 years at one center. Treatment outcomes were classified based on Hurley staging, physician exam, and symptom progression. Adverse effects and concomitant treatment with dapsone were reviewed. RESULTS: Nineteen (19) patients with moderate-to-severe (Hurley Stage II-III) HS treated with oral dapsone were identified. Within 1-3 months, on dosages of dapsone varying from 25-100 mg/day, 3 patients (15.8%) had a clinically significant improvement in symptoms, 10 patients (52.6%) had a slight improvement, and 6 patients (31.6%) had no change in disease state; no patients deteriorated. The majority who improved were also on other medications, most commonly adalimumab. 4 patients experienced adverse effects, with nausea being most common; otherwise, dapsone was well-tolerated. CONCLUSIONS: Dapsone may have some efficacy for moderate-to-severe HS and seems well-tolerated. J Drugs Dermatol. 2023;22(11):e12-e16    doi:10.36849/JDD.4936e.

Systemic non-steroidal immunomodulators for oral lichen planus treatment-a scoping review.

OBJECTIVE: The aim of this scoping review was to evaluate the efficacy and safety of the use of systemic nonsteroidal immunomodulators (SNSI) for oral lichen planus (OLP) treatment. MATERIALS AND METHODS: This review was conducted according to PRISMA-ScR guidelines and registered at PROSPERO (CRD42021243524). Consulted databases were Pubmed, Embase, Scopus, and Web of Science. The inclusion criteria was as follows: clinical trials, case series, prospective, and retrospective studies conducted with participants presenting OLP of any sex and age. RESULTS: Thirty-two studies were selected, assessing 9 different SNSI: methotrexate, dapsone, levamisole, hydroxychloroquine, thalidomide, metronidazole, azathioprine, mycophenolate mofetil, and colchicine. Methotrexate and dapsone were the drugs with the best evidence among the options included, regarding number and quality of studies. Methotrexate resulted in significant improvement in the clinical condition and remission of symptoms, ranging between 63 and 93% of cases. Dapsone presented a similar effect to the use of topical corticosteroids and tacrolimus CONCLUSION: Among SNSI therapeutic options, methotrexate, and dapsone showed promising efficacy and safety. However, large-scale randomized clinical trials are still needed. CLINICAL RELEVANCE: SNSI have been used in the treatment of recalcitrant OLP; however, so far, it is not clear which are the best options. This scoping review highlights the potential use of methotrexate and dapsone.

Dapsone-Loaded Mixed Micellar Gel for Treatment OF Acne Vulgaris.

Mixed polymeric micelles are potential nanocarriers for topical drug delivery. Dapsone (DAP) is an antibacterial used as anti-acne agent, but challenged by low water solubility and poor skin permeability. In the present study, DAP-loaded mixed micellar gel was developed comprising Pluronics F-68 and F-127. Micelles were prepared by solvent evaporation method and particle size, ex vivo permeation, drug loading, and entrapment efficiency were determined. Central Composite Design was used to optimize formulation. Independent variables were concentration of Pluronics at three levels while micelle size and drug loading capacities were dependent variables. Droplet size ranged from 400 to 500 nm. Transmission electron microscopy revealed spherical morphology of micelles. Optimized micelles were incorporated into gel base using HPMC K100M, Sodium CMC, and Carbopol 980 as gelling agents. Gels were evaluated for pH, drug content, spreadability, rheology, syneresis, ex vivo permeation, and subacute dermal toxicity. Compared with solubility of free DAP (0.24+0.056 µg/ml), solubility in mixed micelles was 18.42±3.4 µg/ml in water at room temperature. Order of spreadability of gels was Na CMC < HPMC < Carbopol 980. Carbopol gels displayed thixotropy with index of 3.17. Syneresis for all gels from day 0 to day 30 was found to be in range of 4.2 to 15.6% w/w. Subacute dermal toxicity studies showed no signs of erythema and edema on rat skin until 21 days. These results suggest that mixed micelles can significantly increase solubility and permeability and sustain release of DAP and are suitable carriers for topical DAP delivery in anti-acne therapies.

Erythema elevatum diutinum in a patient with rheumatoid arthritis.

Erythema elevatum diutinum (EED) is a rare cutaneous neutrophilic vasculitis with many associated diseases reported in the literature. We report a 65-year-old woman with painful and itchy lesions on her elbows, hands, knees, and foot for a year. Histopathologic examination confirmed the diagnosis of erythema elevatum diutinum and treatment with dapsone produced significant clinical improvement within few weeks. Erythema elevatum diutinum is a rare disease that should be considered in patients with violaceous nodular plaques located over the extensor regions of the limbs. Knowledge of this unusual pathology and its association helps to avoid misdiagnosis and late treatment.

Leprosy in the Heartland.

BACKGROUND: Mycobacterium leprae is an acid fast bacterium that causes leprosy, also known as Hansen's disease. M. leprae spreads primarily through respiratory droplets and skin contact, and widespread migration of the human population may lead to infection in non-endemic areas. Leprosy mainly affects the skin, peripheral nerves, mucosa of the upper respiratory tract, and the eyes, presenting as a spectrum of disease based on the host immune response consisting of skin lesions, areas of anesthesia, local tissue destruction, and even blindness or glomerulonephritis in severe cases. CASE DESCRIPTION: We describe a case of leprosy presenting in a South Dakota resident. Before this case, leprosy had not been reported in South Dakota in 11 years. The patient presented with chronic skin lesions with areas of anesthesia on her right knee and left elbow. Physical exam was unremarkable aside from the skin lesions, which had areas of decreased sensation over the involved skin. Biopsy of the lesions was positive for noncaseating granulomas with lymphocytic infiltrate that were acid-fast bacillus positive. The biopsy was sent to the National Hansen's Disease Program for further molecular testing, which confirmed M. leprae infection. The patient underwent 12 months of dapsone 100 mg po qd and rifampin 600 mg po qd per U.S. guidelines from the National Hansen's Disease Program Clinical Center. The patient responded well to treatment until developing a reversal reaction after nine months, which was resolved with corticosteroid treatment. Both dermatology and infectious disease continue to follow the patient, and she continues to do well with no evidence of recurrence of active infection or evidence of reversal reaction. CONCLUSIONS: It is important that clinicians be aware of the possibility of uncommon presentations/diseases such as leprosy in areas where it is extremely rare (such as South Dakota) due to immigration and travel among patients. The rarity of leprosy in areas like South Dakota, in addition to its potential for misdiagnosis, may lead to delay of treatment in the patient. Delays in treatment can allow progression of the disease causing skin lesions and possible nerve damage.

Antimicrobial Resistance among Leprosy Patients in Brazil: Real-World Data Based on the National Surveillance Plan.

Brazil ranks second among countries for new cases and first for relapse cases of leprosy worldwide. The Mycobacterium leprae Resistance Surveillance Plan was established. We aimed to present the results of a 2-year follow-up of the National Surveillance Plan in Brazil. A cross-sectional study of leprosy cases was performed to investigate antimicrobial resistance (AMR) in Brazil from October 2018 to September 2020. Molecular screening targeting genes related to dapsone (folP1), rifampin (rpoB), and ofloxacin resistance (gyrA) was performed. During the referral period, 63,520 active leprosy patients were registered in Brazil, and 1,183 fulfilled the inclusion criteria for molecular AMR investigation. In total, only 16 (1.4%) patients had genetic polymorphisms associated with AMR. Of these, 8 (50%) had cases of leprosy relapse, 7 (43.8%) had cases of suspected therapeutic failure with standard treatment, and 1 (6.2%) was a case of new leprosy presentation. M. leprae strains with AMR-associated mutations were found for all three genes screened. Isolates from two patients showed simultaneous resistance to dapsone and rifampin, indicating multidrug resistance (MDR). No significant relationship between clinical variables and the presence of AMR was identified. Our study revealed a low frequency of AMR in Brazil. Isolates were resistant mainly to dapsone, and a very low number of isolates were resistant to rifampin, the main bactericidal agent for leprosy, or presented MDR, reinforcing the importance of the standard World Health Organization multidrug therapy. The greater frequency of AMR among relapsed patients supports the need to constantly monitor this group.