A mixed methods study on factors that promote and ameliorate burnout in academic dermatologists.

The burnout literature is replete with burnout score results from quantitative surveys. There is a paucity of qualitative research that seeks to understand the impact of physician stressors on work-life balance and burnout. This study aimed to identify factors that support and disrupt work-life balance, drivers of burnout, and potential solutions among academic dermatologists. The objective was to better understand factors that promote wellness and ameliorate burnout. Concurrent explanatory mixed methods consisted of scores on the Abbreviated Maslach Burnout Inventory and open-ended semi-structured telephone interviews. The results were that positive factors, such as supportive home life and satisfaction derived from academic endeavors, compete with ongoing feelings of exhaustion, frustration, and apathy. Negative stressors include the electronic medical record, insufficient staffing, administrative and clinical task burden, and perceived lack of interest from mid-level and senior health system leadership in addressing clinicians' needs. This was a single-center academic study. As with all qualitative studies, these results may not be generalizable to all dermatologists. In addition, some participants were concerned about their anonymity. Modifiable root causes of burnout require institutional commitment to sustain the pace required by academic dermatologists.

Low-Dose Total Skin Electron Beam Therapy as Part of a Multimodality Regimen for Treatment of Sézary Syndrome: Clinical, Immunologic, and Molecular Analysis.

Importance: Sézary syndrome (SS) is an advanced form of cutaneous T-cell lymphoma with few long-term remissions observed. Objective: To profile 3 patients with SS who have experienced long-term remission following the addition of low-dose total skin electron beam therapy (TSEBT) to systemic regimens of extracorporeal photopheresis, bexarotene, and interferon-γ. Design, Setting, and Participants: This is a retrospective case series with additional investigations of patient-donated samples to assess therapeutic response. The study was conducted at the University of Pennsylvania Cutaneous Lymphoma Clinic and follows 3 patients with stage IVA1 CD4+ SS who presented to the clinic between November 1, 2009, and November 1, 2017, and who had a history of SS that was refractory to multimodality systemic therapy prior to receiving low-dose TSEBT. Interventions: Patients were treated in a multimodality fashion with combined extracorporeal photopheresis, bexarotene, interferon-γ, and low-dose TSEBT. Main Outcomes and Measures: To characterize treatment responses in these patients, the extent of skin disease was measured with the modified severity weighted assessment tool. Blood disease was measured with flow cytometric assessments of Sézary cell count, CD4:CD8 ratio, and high throughput sequencing of the T-cell receptors. To assess for restoration of immune function, we measured markers of immune exhaustion, including PD-1 (programmed cell death 1), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains), CTLA4 (cytotoxic T-lymphocyte-associated protein 4), TOX (thymocyte selection-associated high mobility group box protein), and Foxp3 (forkhead box P3) on circulating CD4 and CD8 T cells, along with production capacity of interferon-γ by lymphocytes following activation stimuli. Results: Following administration of low-dose TSEBT and maintenance of the other therapies, remissions ranged from 24 to 30 months, with complete responses in 2 patients ongoing. Markers of immune exhaustion including PD-1, TIGIT, CTLA4, TOX, and Foxp3 were significantly reduced from baseline following TSEBT, along with enhanced production capacity of interferon-γ by lymphocytes following activation stimuli. High throughput sequencing demonstrated near-complete eradication of the circulating clone among 2 of 3 patients with stable levels in 1. Conclusions and Relevance: We describe 3 patients who achieved long-term clinical and molecular remissions following low-dose TSEBT as part of a multimodality regimen for treatment of SS. As long-term remissions in SS are uncommon, this approach demonstrates promise, and clinical trials should be considered.

Brentuximab Vedotin for Relapsed or Refractory Sézary Syndrome.

Importance: Treatment options for Sézary syndrome (SS) are limited and associated with low response rates. Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for refractory CD30-positive cutaneous T-cell lymphoma. However, limited data exist on its efficacy in SS, including in the pivotal phase 3 ALCANZA (A Phase 3 Trial of Brentuximab Vedotin (SGN-35) Versus Physician's Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma) trial. Objective: To assess the preliminary efficacy and tolerability of brentuximab vedotin for SS. Design, Setting, and Participants: From January 1, 2017, to July 31, 2020, a total of 13 patients with SS received brentuximab vedotin and were analyzed as part of a retrospective case series. Median follow-up was 10.4 months (range, 1.4-34.6 months). All patients were 18 years or older with a diagnosis of SS and with B2 blood involvement at the time brentuximab vedotin therapy was initiated. This single-center study was conducted at a major academic referral center. Interventions: Intravenous brentuximab vedotin administration approximately every 3 weeks. Main Outcomes and Measures: The primary end point was the global response rate. Outcomes were assessed in the skin and lymph nodes per the 2011 European Organization for Research and Treatment of Cancer-International Society of Cutaneous Lymphoma response criteria and in the blood per the 2018 Prospective Cutaneous Lymphoma International Prognostic Index revised blood response criteria. Results: The study included 13 patients (8 [62%] male; mean [SD] age, 68.2 [8.6] years). Of these 13 patients, 5 (38%) achieved a global response after a median of 6 cycles, including 1 complete response. Response rates by disease compartment were 38% in the skin, 63% in the blood, and 50% in the lymph nodes. Three of 11 patients (27%) with pruritus reported improvement. Skin CD30 positivity (>10%) was detected in 9 patients but was not associated with responses. Among responders, the median time to response was 6 weeks (range, 6-9 weeks), and the median duration of response was 5.5 months (range, 2.5-28.9 months). The median time to next treatment was 3.2 months (range, 1.5-36.7 months). Peripheral neuropathy occurred in 4 patients but resolved in 2 patients. Grade 2 adverse events were neuropathy (n = 2), constipation (n = 1), and hand-foot syndrome (n = 1). Conclusions and Relevance: In this case series, brentuximab vedotin use was associated with some efficacy in SS across multiple disease compartments and in the setting of refractory disease or low CD30 skin expression. Brentuximab vedotin may offer a manageable treatment schedule and low incidence of significant toxic effects.

Cutaneous T-cell lymphoma and concomitant atopic dermatitis responding to dupilumab.

Cutaneous T-cell lymphoma (CTCL) represents a diagnostic challenge because of its large symptomatic overlap with other common skin conditions such as atopic dermatitis (AD) and psoriasis. Dupilumab has offered promising results in AD treatment; however, concerns exist that its use may exacerbate undiagnosed CTCL. We present a patient with CTCL and concomitant AD who experienced improvement in both CTCL blood involvement and AD following the addition of dupilumab therapy.

Expediting patient appointments with dermatology rapid access clinics.

BACKGROUND: Lengthy wait times for dermatology appointments in the U.S. limit care access. The University of Pennsylvania's Department of Dermatology has established an urgent care clinic (UCC) and an intermediate care clinic (ICC) to expedite appointments for higher acuity patients. OBJECTIVE: To describe our rapid access clinics' operations, referral patterns, and distributions of diagnoses. METHODS: We performed a retrospective review of dermatology consult order and appointment data for UCC, ICC, and routine care to determine the number of orders, consult appointments, and follow-up appointments; appointment wait times; and frequencies of diagnoses in referring provider and consult appointments. Press Ganey patient satisfaction ratings were also analyzed. RESULTS: The median (interquartile range) wait times for UCC, ICC, and routine care, appointments were 3 (1-8) days, 36 (15-64) days, and 45 (12-97) days, respectively (P<0.001). The proportion of referrals originating from subspecialists varied among UCC (47.6%), ICC (20.2%) and routine care (15.8%), (P<0.001). Distributions of diagnoses differed among UCC, ICC, and routine care. Ratings for most satisfaction metrics were similar across clinic settings. CONCLUSIONS: Dermatology rapid access clinics within an academic medical center can reduce wait times for higher acuity patients while maintaining patient satisfaction.

Gain of CD26 expression on the malignant T-cells in relapsed erythrodermic leukemic mycosis fungoides.

Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction studies and high-throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.

Improved pruritus correlates with lower levels of IL-31 in CTCL patients under different therapeutic modalities.

Pruritus is one of the cardinal symptoms found in patients with leukemic cutaneous T cell lymphoma (CTCL). The nature of the pruritus experienced by CTCL patients is complex, involving different pathways and cell mediators, thus making it poorly responsive to conventional anti-itch therapies. Recent reports highlight the role of interleukin 31 (IL-31) as a novel cytokine involved in the pathogenesis of pruritus in atopic dermatitis and CTCL. Here we provide both in vivo and in vitro evidence suggesting that histone deacetylase (HDAC) inhibitors may mitigate itch through lowering of levels of IL-31-expressing T cells. Furthermore, we demonstrate that chemokine receptor type-4 (CCR4)-bearing T cells are a main source of IL-31 in CTCL, and that neutralizing the IL-31 pathway through targeting of the CCR4-expressing T cells may represent a promising therapeutic strategy for symptomatic relief in CTCL.

Reliability and convergent validity of the cutaneous sarcoidosis activity and morphology instrument for assessing cutaneous sarcoidosis.

IMPORTANCE: A validated scoring system is essential to assess the effect of therapeutic interventions on a disease. The instrument introduced here captures sarcoidosis disease activity in a reliable, reproducible manner, which will help standardize clinical trial outcomes and allow comparative efficacy studies in the future and may help lead to more robust data regarding the effect of different treatments on cutaneous sarcoidosis. OBJECTIVE: To assess the reliability and convergent validity of the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) and Sarcoidosis Activity and Severity Index (SASI) for evaluating cutaneous sarcoidosis outcomes. DESIGN AND SETTING: Cross-sectional study evaluating cutaneous sarcoidosis disease severity using CSAMI, SASI, and Physician's Global Assessment (PGA) as reference in the dedicated cutaneous sarcoidosis clinic of a teaching hospital. PARTICIPANTS: Eight dermatologists evaluating cutaneous sarcoidosis in 11 patients. INTERVENTION: Evaluation using the study instruments. MAIN OUTCOMES AND MEASURES: Primary outcomes included interrater and intrarater reliability and convergent validity; secondary outcomes, correlation with quality-of-life measures and time required for completion. RESULTS: All instruments demonstrated good to excellent intrarater reliability. Interrater reliability was excellent for CSAMI Activity scores (intraclass correlation coefficient, 0.82 [95% CI, 0.66-0.94]) and fair to poor for CSAMI Damage scores (0.42 [0.21-0.72]), modified Facial SASI (0.40 [0.17-0.72]), and PGA scores (0.40 [0.18-0.70]). CSAMI Activity and Damage scores and modified Facial SASI all demonstrated convergent validity with statistically significant correlations with PGA scores. Trends for correlations were seen between CSAMI scores and specific Skindex-29 quality-of-life domains. Although CSAMI required longer time to complete than SASI, both were scored within adequate time for use in clinical trials. CONCLUSIONS AND RELEVANCE: CSAMI appears to be a reliable and valid outcome instrument to measure cutaneous sarcoidosis and may capture a wide range of body surface and cutaneous morphologic types. This instrument can be adopted into clinical practice and clinical trials to allow physicians to assess the intensity of their patients' cutaneous sarcoidosis disease activity. Widespread use of one metric for disease severity assessment can help standardize the evaluation of the effect of various treatments on the disease. Future research is necessary to demonstrate its sensitivity to change and to confirm its correlation with quality-of-life measures.

Improvement in peripheral blood disease burden in patients with Sézary syndrome and leukemic mycosis fungoides after total skin electron beam therapy.

BACKGROUND: There is a paucity of effective therapies for patients with Sézary syndrome and advanced mycosis fungoides with peripheral blood involvement. Total skin electron beam (TSEB) radiation therapy is an extremely effective skin-directed therapy for these patients, but, until recently, it was thought not to signifcantly affect the peripheral blood malignant T-cell population. OBJECTIVE: We conducted this study to determine if TSEB has therapeutic effect on the peripheral blood in patients with advanced mycosis fungoides and Sézary syndrome. METHODS: All patients on stable medication regimens seen in our photopheresis facility who received TSEB therapy between January 2008 and October 2011 at Temple University Hospital, Philadelphia, PA, were analyzed retrospectively for improvement in the peripheral blood, as documented by flow cytometry. RESULTS: Six of 11 patients achieved 50% or greater decrease in their peripheral blood malignant T-cell population after TSEB therapy, for an overall response rate of 55%. Within the group of patients who had a response in the skin, 67% also had a response in the peripheral blood. LIMITATIONS: This analysis is limited in 3 ways. First, the sample described is small. Second, the results may be confounded by the fact that each patient was on other systemic therapies in addition to TSEB, albeit stable pre-existing regimens. The time interval between completion of TSEB therapy and repetition of flow cytometry was not standardized among patients, which may result in an underestimation of the overall response to TSEB therapy. CONCLUSION: In patients with advanced mycosis fungoides and Sézary syndrome, the peripheral blood tumor burden may improve after treatment with TSEB.

Peripheral blood findings in erythrodermic patients: importance for the differential diagnosis of Sézary syndrome.

Although Sézary syndrome (SS) represents an advanced stage of cutaneous T-cell lymphoma, this diagnosis presents a challenge even for the most experienced dermatologic clinicians. SS is characterized clinically by erythroderma, but can also be identified in the presence of specific histologic and peripheral blood findings. Erythrodermic cutaneous T-cell lymphoma can mimic a number of nonmalignant disorders with erythroderma, including pityriasis rubra pilaris, psoriasis, atopic dermatitis, and graft-versus-host disease. The diagnosis is made even more challenging because the histology of SS is often nonspecific and rarely pathognomonic. As a result, peripheral blood studies in patients with erythroderma are frequently informative in the diagnosis of SS. Peripheral blood abnormalities including elevated CD4/CD8 ratio, aberrant CD26, CD27 and CD7 expression, and T-cell clonality can all be used to help arrive at a diagnosis. This review evaluates current data on the usefulness and limitations of specific peripheral blood markers detected by flow cytometry and T-cell receptor gene rearrangement polymerase chain reaction.

Inhibition of cell-mediated immunity by the histone deacetylase inhibitor vorinostat: implications for therapy of cutaneous T-cell lymphoma.

Several histone deacetylase inhibitors (HDACi), including vorinostat, have been approved for the therapy of cutaneous T-cell lymphoma (CTCL). Emerging data suggest that HDACi may exert immune suppressive effects which would be disadvantageous for therapy of CTCL. We describe a patient with Sezary syndrome who was monitored for drug-induced immunosuppression while undergoing treatment with vorinostat. Analysis of the patient's natural killer cell function before and after initiation of treatment confirmed inhibition of this important cell-mediated immune function. In addition, the in vitro effects of vorinostat on the immunity of healthy volunteers confirmed that this class of drug can profoundly suppress multiple arms of the cellular immune response. These findings raise concerns of increased susceptibility to infection in this high-risk population.