Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Racial Disparities in Mycosis Fungoides/Sézary Syndrome-A Single-Center Observational Study of 292 Patients.

BACKGROUND: Clinical presentation of Mycosis fungoides/Sézary syndrome (MF/SS) in Black and African American (AA) patients can be heterogeneous with poor survival reported in AA/black patients. In this study, we aim to characterize differences between AA/black and white patients with MF/SS. PATIENTS AND METHODS: A retrospective single-center hospital-based case-control study including 292 MF/SS patients (146 AA/black matched with 146 white patients). We analyzed demographic, clinical and survival differences. RESULTS: AA/black patients were diagnosed at an earlier age (9 years younger), were predominantly females, had higher rates of Medicaid/Medicare insurance and lower income compared to matched white patients (P <.001). Adjusting for age, sex, insurance type, and income bracket, AA/black patients had significantly worse overall survival (hazard ratio [HR] 2.88, 95%CI 1.21-6.85, P = .017). Association of clinical MF phenotype with survival showed that hypopigmentation was associated with survival in AA/black patients but not in white patients. Erythroderma and ulceration were associated with worse survival risk in AA/black patients. CONCLUSIONS: AA/black patients with MF/SS have a significant worse survival outcome compared to white patients. The association between clinical phenotypes and survival differed between these groups. Further studies are required to investigate whether race-specific pathogenesis or genetic factors may explain these differences.

Non-invasive Skin Imaging in Cutaneous Lymphomas.

The diagnosis of cutaneous lymphomas is challenging and requires skin tissue for histology and immunophenotyping using immunohistochemistry and molecular studies. In recent years, the role of non-invasive imaging techniques has been described as part of the clinical assessment of cutaneous lymphoma lesions. Imaging modalities such as dermoscopy, reflectance confocal microscopy (RCM), and high frequency ultrasound (HFUS) have been shown to be very valuable in raising the clinical suspicion for lymphomas of the skin, and in distinguishing cutaneous lymphomas from inflammatory dermatoses such as lupus, psoriasis, or eczema. These non-invasive methods can be used to direct the clinician to the optimal biopsy site to maximize the histopathological results and minimize false negatives. These methods also have a potential place in monitoring treatment response. In this review we present a concise summary of the dermoscopic imaging, RCM, and HFUS features seen in cutaneous T-cell lymphomas (CTCL) and B-cell lymphomas (CBCL).

Advances in the treatment of mycoses fungoides and Sézary syndrome: a narrative update in skin-directed therapies and immune-based treatments.

Mycoses fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas that are often challenging to manage given the absence of reliably curative therapies, at times high symptom burden with significant detriment to quality of life, and need for ongoing treatment for disease and symptom control. Recent developments in skin-directed treatments include optimizing the use of existing topical therapies, the introduction of known dermatological agents and treatment modalities for the specific treatment of MF/SS (such as mechlorethamine gel, calcineurin inhibitor creams, and photodynamic therapy), and novel local and topical agents. For advanced disease, dedicated clinical trials have translated to exciting progress, leading to the approval of brentuximab vedotin (2017) and mogamulizumab (2018) for relapsed MF/SS. Additional studies of other active systemic agents, including various cellular therapies, represent further attempts to add to the therapeutic armamentarium in treating MF/SS. In this review, we highlight these recent advancements, ranging from optimization of skin-directed therapies to the introduction of novel systemic agents. We focus on therapies approved in the preceding five years or under investigation in advanced-phase clinical trials.

International Dermoscopy Society (IDS) Criteria for Skin Tumors: Validation for Skin of Color Through a Delphi Expert Consensus by the "Imaging in Skin of Color" IDS Task Force.

INTRODUCTION: A structured set of eight basic dermoscopic parameters (lines, clods, dots, circles, pseudopods, structureless, else, and vessels) including a total of 77 variables with corresponding descriptive and metaphoric vocabulary has been released for evaluation of skin tumors by the International Dermoscopy Society (IDS). OBJECTIVES: To validate the aforementioned criteria for the use in darker phototypes (phototypes IV-VI) via an expert consensus. METHODS: The two-round "Delphi method" was adopted, with an iterative process including two rounds of email questionnaires. Potential panelists were asked to take part in the procedure via email on the basis of their expertise in the dermoscopy of skin tumors in dark phototypes. RESULTS: A total of 17 participants were involved. All the original variables of the eight basic parameters reached agreement during the first round, except for "pink small clods" ("milky red globules") and "structureless pink zone" ("milky red areas"). Moreover, during the first round, panelists proposed a change of three existing items and the introduction of four new items, i.e., "black, small clods" ("black globules"), "follicular plugs", "erosions/ulcerations", and "white color around vessels" ("perivascular white halo"). All such proposals achieved agreement, thus being included in the final list, for a total of 79 items. There was consistency between the descriptive and metaphoric approaches in terms of scoring. CONCLUSIONS: Albeit most of the original items were considered applicable even for skin of color, there are some points of differences that physicians need to know. No significant preference was found between descriptive and metaphoric terminology among panelists.

T-Cell Monoclonality in the Blood and the Skin Correlates With Poor Response to Treatment in Mycosis Fungoides.

BACKGROUND: The prognostic value of skin and blood T-cell receptor clonality in mycosis fungoides is a matter of debate. Our aim was to ascertain the relation between the presence of a monoclonal T-cell population in the blood and in the skin with response to treatment in patients with mycosis fungoides. PATIENTS AND METHODS: Clinical features and follow-up data were retrospectively collected and analyzed in 94 patients with mycosis fungoides seen at a cutaneous lymphoma clinic in a single tertiary center. All patients had results of polymerase chain reaction analysis of T-cell receptor gamma gene rearrangement in lesional skin and in peripheral blood at time of diagnosis. Association of response to treatment with clonality in the tissue and in the blood was assessed. RESULTS: T-cell monoclonality was detected in the skin in 30 of 94 patients, in the blood in 12 of 94 cases and the same clone was found in both tissues in 6 of 94 patients. The presence of a polyclonal T-cell population in the circulation was associated with complete response (P = .006). Lack of response to treatment (stable disease or progression of disease) was associated with T-cell clonality in skin (P = .009), in blood (P = .002) and in both tissues (P < .001). A multivariate analysis showed that T-cell monoclonality in the skin is independently associated with lack of response of mycosis fungoides to therapy. CONCLUSION: Blood and skin should be studied for T-cell clonality as part of the routine initial workup, even in patients with early-stage disease.

Improving Hospital Outpatient Clinics Appointment Schedules by Prediction Models.

Patient no-shows and suboptimal patient appointment length scheduling reduce clinical efficiency and impair the clinic's quality of service. The main objective of this study is to improve appointment scheduling in hospital outpatient clinics. We developed generic supervised machine learning models to predict patient no-shows and patient's length of appointment (LOA). We performed a retrospective study using more than 100,000 records of patient appointments in a hospital outpatient clinic. Several machine learning algorithms were used for the development of our prediction models. We trained our models on a dataset that contained patients', physicians', and appointments' characteristics. Our feature set combines both unstudied features and features adopted from previous studies. In addition, we identified the influential features for predicting LOA and no-show. Our LOA model's performance was 6.92 in terms of MAE, and our no-show model's performance was 92.1% in terms of F-score. We compared our models' performance to the performance of previous research models by applying their methods to our dataset; our models demonstrated better performance. We show that the major effector of such differences is the use of our novel features. To evaluate the effect of our prediction results on the quality of schedules produced by appointment systems (AS), we developed an interface layer between our prediction models and the AS, where prediction results comprise the AS input. Using our prediction models, there was an 80% improvement in the daily cumulative patient waiting time and a 33% reduction in the daily cumulative physician idle time.

Severe cutaneous adverse reactions associated with systemic ivermectin: A pharmacovigilance analysis.

Despite poor evidence, the antiparasitic ivermectin has been advocated as a potential COVID-19 therapy. This has led to a rise in calls to poison-control centers by people self-medicating with ivermectin, which is sold over the counter for veterinary uses. We aimed to investigate the association between severe cutaneous adverse reactions (SCARs) and ivermectin. Postmarketing data from the FDA Adverse Event Reporting System (FAERS), gathered between 2014 and 2021, was employed to detect disproportional signals of SCARs following systemic ivermectin therapy. The reporting odds ratio (ROR) was used to quantify the strength of association, while adjusting for age, sex, and region. The search yielded 517 reports of systemic ivermectin (median age 54 years, 46.8% female), of which 25 (4.8%), 81 (15.7%), and 411 (79.5%) were classified as SCARs, nonsevere cutaneous adverse events (AEs), or noncutaneous AEs, respectively. The regional distribution differed between SCAR reports (32.0% from Africa and 12.0% from North America) compared with other AEs, which originated from North America in over half of cases. The most common SCARs were toxic epidermal necrolysis (seven cases), Stevens-Johnson syndrome (seven cases), and drug reaction with eosinophilia and systemic symptoms (four cases). Five SCAR cases (20.0%) resulted in death and 12 (48.0%) lead to hospitalization. There was a strong safety signal for any SCAR (adjusted ROR 3.34, 95% confidence interval [CI] 2.17-5.12) and toxidermias (adjusted ROR 7.08, 95% CI 4.23-11.84). This study suggests that ivermectin is associated with SCARs on rare occasions. Dermatologists should be aware of this given the increase in ivermectin misuse.

CRP Levels as a Prognostic Factor in Mycosis Fungoides.

Mycosis Fungoides (MF) and Sézary syndrome (SS) are the most common forms of cutaneous T-cell lymphomas. Few validated prognostic factors have been reported in MF/SS, especially when compared with non-cutaneous lymphomas. Increased C-reactive protein (CRP) levels have recently been associated with poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of serum CRP levels at diagnosis in patients with MF/SS. This retrospective study included 76 patients with MF/SS. Stage was assigned according to the ISCL/EORTC guidelines. The follow-up period was 24 months or more. Disease course and response to treatment were determined using quantitative scales. Wilcoxon's rank test and multivariate regression analysis were used to analyze the data. Increased CRP levels correlated significantly with advanced stages (Wilcoxon's test, P>0.0001). Furthermore, increased CRP levels were associated with a lower treatment response rate (Wilcoxon's test, P=0.0012). Multivariate regression analysis showed that CRP is an independent predictor of advanced clinical stage at diagnosis.The present data suggest that elevated CRP levels could serve as a useful prognostic factor in MF/SS and may assist in guiding treatment choices.

Dermatoscopy of nodular/plaque-type primary cutaneous T- and B-cell lymphomas: A retrospective comparative study with pseudolymphomas and tumoral/inflammatory mimickers by the International Dermoscopy Society.

BACKGROUND: Limited data on dermatoscopy of nodular/plaque-type T-/B-cell primary cutaneous lymphomas (PCLs) is available. OBJECTIVE: To describe dermatoscopic features of nodular/plaque-type PCLs, comparing them with those of clinical mimickers (pseudolymphomas, tumors, and inflammatory lesions) and investigating possible differences according to histologic subtypes. METHODS: Participants were invited to join this retrospective, multicenter case-control study by submitting histologically/immunohistochemically confirmed instances of nodular/plaque-type PCLs and controls. Standardized assessments of the dermatoscopic images and comparative analyses were performed. RESULTS: A total of 261 lesions were included (121 PCLs and 140 controls). Orange structureless areas were the strongest PCL dermatoscopic predictor on multivariate analysis compared with tumors and noninfiltrative inflammatory dermatoses. On the other hand, a positive association was found between PCLs and either unfocused linear vessels with branches or focal white structureless areas compared with infiltrative inflammatory dermatoses, whereas white lines were predictive of PCLs over pseudolymphomas. Differences in the vascular pattern were also seen between B- and T-cell PCLs and among B-cell PCL subtypes. LIMITATIONS: Retrospective design and the lack of a dermatoscopic-pathologic correlation analysis. CONCLUSION: Nodular/plaque-type PCLs display dermatoscopic clues, which may partially vary according to histologic subtype and whose diagnostic relevance depends on the considered clinical differential diagnoses.

FOXP3 Predicts Response to Treatment in Mycosis Fungoides.

BACKGROUND: The role of the T-regulatory cells (Tregs) marker forkhead box Protein 3 (FOXP3) in mycoses fungoides (MF) pathogenesis is unclear and the results of previous studies are inconclusive. OBJECTIVE: We aimed at ascertaining the possibility that FOXP3 expression may serve to predict MF stage and response to therapy. PATIENTS AND METHODS: Immunohistochemistry staining for FOXP3 was performed on 30 skin biopsies from patients with MF, and FOXP3 expression level was quantitatively graded. Disease stage, progression, and response to treatment were determined based on clinical and imaging evidence, and association with FOXP3 expression was assessed. RESULTS: FOXP3 expression in the dermis correlated with poor response to treatment (P=0.047). A negative non-significant relationship between epidermal FOXP3 expression and clinical stage severity was observed (P=0.17). CONCLUSIONS: Dermal FOXP3 expression in MF lesions could be used to predict response to treatment in patients with MF.

Primary Cutaneous B-Cell Lymphomas in Children and Adolescents: A SEER Population-Based Study.

BACKGROUND: Although primary cutaneous B-cell lymphomas (PCBCL) comprise 25% of all cutaneous lymphomas, their incidence in the pediatric population is unknown, and the information on pediatric PCBCL has mostly been gathered from individual case reports or series from single centers. PATIENTS AND METHODS: This was a population-based, retrospective cohort study of patients in 18 cancer registries in the United States diagnosed between 2000 to 2016 through the Surveillance, Epidemiology, and End Results (SEER) program. Age-adjusted incidence rates were calculated for PCBCL in pediatric (<20 years) and adult (≥20 years) populations. Demographic, clinical, and pathological characteristics of PCBCL were compared between the two groups. RESULTS: A total of 48 pediatric and 5128 adult PCBCL cases were included. Median age at diagnosis was 16.5 years and 65 years in the two groups, respectively. The major histologic subtypes of pediatric cases were marginal zone lymphoma (77.1%), followed by diffuse large B-cell lymphoma (12.5%) and follicle center lymphoma (10.4%), which were equally distributed in adults. The age-adjusted pediatric PCBCL incidence rate (per 1,000,000 person-years) was 0.12 (95% CI 0.09-0.16). The incidence in the adult population was approximately 40-fold higher than the one observed in the pediatric group (IRR 41.4, 95% CI 31.2-56.2). All 48 pediatric cases were alive during a median follow-up time of 48 months. CONCLUSIONS: Pediatric PCBCL is a very rare disease affecting mostly adolescents of both sexes. The major histologic subtype is marginal zone lymphoma, and the prognosis is favorable.

Topical clobetasol propionate treatment and cutaneous adverse effects in patients with early-stage mycosis fungoides: an observational study.

Topical superpotent class I corticosteroids (CSs) are highly effective in the treatment of early-stage mycosis fungoides (MF) and are readily available, easily applied, and have minor side effects compared to other topical therapeutic options. Because MF is a chronic disease, prolonged treatment is needed, raising the concern of CS-induced cutaneous adverse effects (AEs). In this observational study, we aimed to evaluate the risk for skin AEs of clobetasol propionate cream 0.05% in patients with early-stage MF. Thirteen consecutive patients with MF were treated with clobetasol propionate cream 0.05% once or twice daily as monotherapy and were followed for 4 to 17 months. One participant was lost to follow-up, and the remaining 12 participants responded to treatment with topical clobetasol propionate with minimal side effects. With proper education and monitoring, topical CSs are a safe and effective mainstay of treatment for patches and flat plaques in patients with early-stage localized MF.