Integrating Precision Medicine into Medical Dermatology Clinical Practice: An Expert Consensus Panel.

BACKGROUND: Precision medicine utilizes an individual’s genomics to improve diagnosis, prognosis, and therapy. The joint American Academy of Dermatology and National Psoriasis Foundation 2019 guidelines recognized the need to identify biomarkers that can predict the optimal biologic agent for an individual patient. This paper examines the current state of precision medicine in dermatology and how its use can improve outcomes in psoriasis. METHODS: A search of PubMed/MEDLINE using the terms precision medicine, personalized medicine, biomarkers, genomics, and dermatology was performed to identify relevant publications. An expert consensus panel was then convened to assign levels of evidence to each article using strength of recommendation taxonomy and create consensus statements requiring a two-thirds supermajority for agreement utilizing a modified Delphi approach. RESULTS: Thirteen articles met inclusion and exclusion criteria and were assigned levels of evidence. The panel created 10 consensus statements on how precision medicine can improve patient outcomes, all of which received a unanimous (6/6) vote. CONCLUSION: Choosing a biologic medication for psoriasis often relies on patient preference, provider preference, and a trial-and-error approach. Utilizing precision medicine tests such as Mind.Px can help providers identify biomarkers unique to a patient’s pathophysiology and choose the optimal medication through a targeted and evidence-based approach. Zakria D, Brownstone N, Armstrong AW, et al. Integrating precision medicine into medical dermatology clinical practice: an expert consensus panel. J Drugs Dermatol. 2023;22(6):588-593. doi:10.36849/JDD.7432.

Mycosis Fungoides: Awareness in Skin of Color.

Over the past decade, what is known about skin of color in the field of dermatology has gained an increasing amount of attention among both clinicians and the general public. Recent efforts have continued to shed light on the role of skin color in health disparities and the development of actionable strategies to improve outcomes for patients of color. While research has largely focused on conditions such as atopic dermatitis, psoriasis, and skin cancer, uncommon dermatologic conditions have been less emphasized in skin of color discussions thus far.

Comparison of racial distribution of photodermatoses in USA academic dermatology clinics: A multicenter retrospective analysis of 1080 patients over a 10-year period.

BACKGROUND: Previous studies at single academic institutions have identified variations in the prevalence of photodermatoses among racial groups. The purpose of the study was to compare the distribution of photodermatoses between Whites and Blacks at four academic medical centers in the USA. METHODS: A retrospective chart review was performed at four institutions' general dermatology clinics using diagnoses consistent with the International Classification of Disease (ICD), Ninth and Tenth Revisions, codes related to photodermatoses between August 2006 and August 2016. A total of 9736 charts were manually reviewed and classified. Analyses were performed analyzing the frequency of photodermatoses between Whites and Blacks in the pooled data. RESULTS: There were 1,080 patients with photodermatoses identified. Statistically significant differences in the frequency of photodermatoses between Whites and Blacks were identified for polymorphous light eruption (more common in Blacks), photoallergic contact dermatitis, phototoxic drug eruption, phytophotodermatitis, porphyria, and solar urticaria (more common in Whites). The most commonly diagnosed photodermatoses were polymorphous light eruption (total 672), and photodermatitis not otherwise specified (total 189). CONCLUSION: Our study demonstrated significantly higher proportions of polymorphous light eruption in Blacks, and higher proportions of photoallergic contact dermatitis, phototoxic drug eruptions, phytophotodermatitis, porphyrias, and solar urticaria in Whites.

Disparities in the Presentation and Management of Cutaneous Melanoma That Required Admission.

OBJECTIVE: In this study, we aimed to examine the association of demographic and socioeconomic factors with cutaneous melanoma that required admission. METHODS: A cross-sectional study utilizing the Nationwide Inpatient Sample database, 2003-2009, was merged with County Health Rankings Data. RESULTS: A total of 2,765 discharge -records were included. Men were more likely to have melanoma in the head, neck, and trunk regions (p < 0.001), while extremities melanoma was more common in women (p < 0.001). Males had a higher risk of lymph node metastasis on presentation (OR 1.54, 95% CI [1.27-1.89]). Blacks and Hispanics were more likely to present with extremities melanoma. Patients with low annual income were more likely to be treated by low-volume surgeons and in hospitals located in high-risk communities (p < 0.05 each). Patients with Medicaid coverage were twice as likely to present with distant metastasis and were more likely to be managed by low-volume surgeons (p < 0.05 each). CONCLUSIONS: The presentation and outcomes of cutaneous melanoma have a distinct pattern of distribution based on patients' characteristics.

Etiologies and management of cutaneous flushing: Nonmalignant causes.

The flushing phenomenon may represent a physiologic or a pathologic reaction. Although flushing is usually benign, it is prudent that the physician remains aware of potentially life-threatening conditions associated with cutaneous flushing. A thorough investigation should be performed if the flushing is atypical or not clearly associated with a benign underlying process. The diagnosis often relies on a pertinent history, review of systems, physical examination, and various laboratory and imaging modalities, all of which are discussed in the 2 articles in this continuing medical education series. This article reviews flushing associated with fever, hyperthermia, emotions, menopause, medications, alcohol, food, hypersensitivity reactions, rosacea, hyperthyroidism, dumping syndrome, superior vena cava syndrome, and neurologic etiologies.

Etiologies and management of cutaneous flushing: Malignant causes.

The second article in this 2-part continuing medical education series reviews the following malignant causes of flushing: mastocytosis, medullary thyroid carcinoma, pheochromocytoma, carcinoid tumors, gastroenteropancreatic neuroendocrine tumors, bronchogenic carcinoma, vasointestinal polypeptide secreting tumors, and renal cell carcinoma. The information provided will allow physicians to better distinguish patients who have worrisome presentations that require a more thorough investigation. Appropriate diagnostic workup and treatment options for these malignancies are reviewed.

From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis.

BACKGROUND: An urgent need exists in the United States to establish treatment goals in psoriasis. OBJECTIVE: We aim to establish defined treatment targets toward which clinicians and patients with psoriasis can strive to inform treatment decisions, reduce disease burden, and improve outcomes in practice. METHODS: The National Psoriasis Foundation conducted a consensus-building study among psoriasis experts using the Delphi method. The process consisted of: (1) literature review, (2) pre-Delphi question selection and input from general dermatologists and patients, and (3) 4 Delphi rounds. RESULTS: A total of 25 psoriasis experts participated in the Delphi process. The most preferred instrument was body surface area (BSA). The most preferred time for evaluating patient response after starting new therapies was at 3 months. The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or more from baseline. The target response at 3 months postinitiation was BSA 1% or less. During the maintenance period, evaluation every 6 months was most preferred. The target response at every 6 months maintenance evaluation is BSA 1% or less. LIMITATIONS: Although BSA is feasible in practice, it does not encompass health-related quality of life, costs, and risks of side effects. CONCLUSION: With defined treatment targets, clinicians and patients can regularly evaluate treatment responses and perform benefit-risk assessments of therapeutic options individualized to the patient.

Treatment of refractory necrobiotic xanthogranulomas with extracorporeal photopheresis and intravenous immunoglobulin.

Necrobiotic xanthogranuloma (NXG) is a disease of fibrotic or telangiectatic granulomatous papules and nodules that can ultimately progress into ulcerated plaques. Although the exact cause of NXG is unknown, it most often occurs in patients with paraproteinemia secondary to a hematologic disease. Consequently, therapy for NXG is targeted at treating the underlying hematologic disease, and subsequent paraproteinemia, with alkylating agents, antimetabolites, radiation, and/or immunosuppressive agents. Cases refractory to these therapies often have poor outcomes. We report the successful treatment of two patients with refractory NXG with two different modalities: extracorporeal photopheresis (ECP) and intravenous immunoglobulin (IVIG). The first case shows a patient without paraproteinemia who had success with ECP and IVIG, and the second is a patient with paraproteinemia treated effectively with IVIG. The beneficial response of our patients to IVIG, as well as ECP, shows that they may be an effective treatment option for refractory NXG.

Utility of hydroxychloroquine laboratory monitoring in dermatologic and rheumatologic patients.

Hydroxychloroquine (HCQ) is an immunomodulator used in dermatology and rheumatology. Side effects may be observed on routine monitoring studies before they become clinically apparent. The goal of this retrospective chart review was to assess laboratory abnormalities in dermatologic and rheumatologic patients taking HCQ. Medical records of patients prescribed HCQ were retrospectively reviewed. Demographics, reported side effects, and parameters on baseline and follow-up complete blood count (CBC) and comprehensive metabolic panel (CMP) were recorded and graded. Laboratory abnormalities were considered severe if they were grade 3 or greater according to Common Terminology Criteria for Adverse Events v3.0 and persistent if they continued beyond subsequent laboratory testing. Of 646 eligible charts, 289 had monitoring studies for review. There were 35 severe (grade 3 or 4, 35/289; 12%) adverse events that developed, as noted on CBC or CMP. Of these 35 severe adverse events, 25 self-corrected on subsequent testing, and 10 (10/289, 3%) across 9 patients were persistent, including glomerular filtration rate, alanine transferase, alkaline phosphatase, glucose, hemoglobin and lymphopenia abnormalities. Of these 10 abnormalities, 7/10 (70%) were unlikely due to hydroxychloroquine use according to the calculated Naranjo score for each patient. Severe laboratory abnormalities while taking hydroxychloroquine are rare, even in a population with a high rate of comorbidities. Among the abnormalities observed, the majority of them (70%) were likely due to disease progression or a medication other than hydroxychloroquine. CBC and CMP monitoring for the reason of observing abnormalities while on HCQ should be at the discretion of the prescribing physician.

Healthcare Provider Experience in Diagnosing and Treating Cutaneous T-Cell Lymphoma.

INTRODUCTION: Cutaneous T-cell lymphoma (CTCL) is a rare, heterogeneous group of non-Hodgkin lymphomas characterized by various clinical, molecular, and histopathologic features of the skin. Variants of CTCL share many clinical features with common inflammatory skin diseases such as atopic dermatitis and psoriasis, making accurate and early diagnosis challenging in clinical settings. Inappropriate treatment or a delay in diagnosis can lead to increased morbidity and mortality. Here, we report findings from an online survey that investigated dermatology community practice, knowledge, and education surrounding CTCL. METHODS: An electronic survey of ten questions was developed and approved by physician experts in CTCL to assess experiences in diagnosing and treating CTCL among healthcare providers (HCPs). The survey was deployed to 10,600 US dermatology HCPs, including medical doctors (MDs), doctors of osteopathic medicine (DOs), nurse practitioners (NPs), and physician assistants (PAs) and excluding HCPs associated with CTCL centers of excellence. RESULTS: Among 44 HCPs who responded and were eligible for inclusion, 82% had diagnosed between one and ten CTCL cases in the last 5 years. Most respondents (91%) reported that they include CTCL in their differential diagnoses after patients do not respond to treatment of more common conditions. Patients with CTCL were frequently diagnosed with other inflammatory dermatoses-most commonly dermatitis and psoriasis-before a CTCL diagnosis, and many were treated with ineffective therapies for years. The most common length of time before a CTCL diagnosis was made was between 1 and 3 years, though 16% of HCPs reported that patients were treated for other diseases or skin conditions for ≥ 5 years. Two-thirds of HCPs agreed that further education surrounding CTCL is needed. CONCLUSIONS: Given the infrequency of CTCL and its similar presentation to other common dermatologic conditions, increased education of CTCL is needed in the dermatology community to improve patient outcomes.

Macrophages in dermatology: pathogenic roles and targeted therapeutics.

The field of macrophage biology is rapidly growing. Recent studies have shifted focus from classic wound healing roles to newly identified roles in dermatologic pathology. These studies have identified pathogenic roles of macrophages in relatively common conditions, such as psoriasis, skin cancer, and cutaneous T-cell lymphoma. Selective depletion of these cells or their associated cytokines leads to improved clinical outcome. Herein, we review recent animal and human studies that have elucidated novel pathogenic roles of macrophages in conditions frequently encountered by dermatologists and discuss clinically relevant macrophage-targeted therapies.

Apremilast in Recalcitrant Cutaneous Dermatomyositis: A Nonrandomized Controlled Trial.

Importance: Cutaneous disease in dermatomyositis has no standardized treatment approach and so presents a challenging task for patients and clinicians. Objective: To study the efficacy and safety of apremilast as an add-on therapy in patients with recalcitrant cutaneous dermatomyositis. Design, Setting, and Participants: This phase 2a, open-label, single-arm nonrandomized controlled trial was conducted at a single center from June 2018 to June 2021. Participants were 8 patients with recalcitrant cutaneous dermatomyositis, defined by a cutaneous disease activity severity index (CDASI) score greater than 5 despite treatment with steroids, steroid-sparing agents, or both. Data were analyzed from June 2018 to June 2021. Interventions: Apremilast 30 mg orally twice daily was added to ongoing treatment regimens. Main Outcomes and Measures: The primary outcome was the overall response rate (ORR) at 3 months. Key secondary outcomes were the safety and toxicity of apremilast and the durability of response at 6 months. The CDASI, muscle score, dermatology life quality index (DLQI), and depression assessments were performed at baseline and regularly until month 7. Skin biopsies were performed at baseline and 3 months after apremilast (defined as 3 months into active apremilast therapy) and tested for gene expression profiling and immunohistochemical stains. Adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0. Results: Among 8 patients with recalcitrant cutaneous dermatomyositis (all women; mean [SD] age, 54 [15.9] years), a response was found at 3 months after apremilast among 7 patients (ORR, 87.5%). The mean (SD) decrease in CDASI was 12.9 (6.3) points at 3 months (P < .001). Apremilast was well tolerated, with no grade 3 or higher adverse events. Sequencing of RNA was performed on skin biopsies taken from 7 patients at baseline and at 3 months after therapy. Appropriate negative (ie, no primary antibody) and positive (ie, tonsil and spleen) controls were stained in parallel with each set of slides studied. Of 39 076 expressed genes, there were 195 whose expression changed 2-fold or more at P < .01 (123 downregulated and 72 upregulated genes). Gene set enrichment analysis identified 13 pathways in which apremilast was associated with downregulated expression, notably signal transducers and activators of transcription 1 (STAT1), STAT3, interleukin 4 (IL-4), IL-6, IL-12, IL-23, interferon γ (IFNγ), and tumor necrosis factor α (TNFα) pathways. In immunohistochemical staining, there was a mean (SD) decrease in phosphorylation levels STAT1 (22.3% [28.3%] positive cells) and STAT3 (13.4% [11.6%] positive cells) at the protein level, a downstream signaling pathway for the downregulated cytokines. Conclusions and Relevance: These findings suggest that apremilast was a safe and efficacious add-on treatment in recalcitrant dermatomyositis, with an overall response rate of 87.5% and associations with downregulation of multiple inflammatory pathways. Trial Registration: ClinicalTrials.gov Identifier: NCT03529955.

Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial.

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.

Therapeutic hotline. Abatacept: our experience of use in two patients with refractory psoriasis and psoriatic arthritis.

The B7 family of molecules on antigen presenting cells (APCs) regulate T cell activation. They deliver stimulatory signals through CD28 and inhibitory signals through CD152, or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). CTLA4Ig (abatacept) is a soluble chimeric protein consisting of the extracellular domain of human CD152 linked to the modified Fc portion of human IgG1. By binding to B7-1 (CD80) and B7-2 (CD86) molecules on APCs, CTLA4Ig blocks the CD28-mediated costimulatory signal for T cell activation. Success with abatacept has been noted in psoriasis. Abatacept was administered to two patients with refractory psoriasis and psoriatic arthritis after the patients had failed all conventional treatment methods. Both patients experienced very brief improvement in disease. The improvement, however, was not continued, and both patients were taken off the medication. The small patient population limits the extrapolation of the present authors' results to the larger population. Furthermore, the present authors' patients have very severe, refractory disease and do not adequately represent the majority of psoriasis patients. Although the present authors' patients demonstrated brief response to drug, this response was not sustained. No adverse events were reported in the present authors' patients.

Effect of Costimulatory Blockade With Abatacept After Ustekinumab Withdrawal in Patients With Moderate to Severe Plaque Psoriasis: The PAUSE Randomized Clinical Trial.

IMPORTANCE: Psoriasis relapse may involve compensatory T-cell activation pathways in the presence of CD28-CD80/CD86 blockade with abatacept. OBJECTIVE: To determine whether costimulatory signaling blockade with abatacept prevents psoriasis relapse after ustekinumab withdrawal. DESIGN, SETTING, AND PARTICIPANTS: Psoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE), a parallel-design, double-blind, placebo-controlled randomized clinical trial, was conducted at 10 sites in the US and Canada. Participant enrollment opened on March 19, 2014, and concluded on April 11, 2016. Participants were adults with moderate to severe plaque psoriasis and received ustekinumab in a lead-in phase. Those who responded to ustekinumab at week 12 were randomized 1:1 to either the continued with ustekinumab group (ustekinumab group) or the switched to abatacept group (abatacept group). Treatment was discontinued at week 39, and participants were followed up for psoriasis relapse until week 88. Statistical analyses were performed in the intention-to-treat (ITT) and safety samples from May 3, 2018, to July 6, 2021. INTERVENTIONS: Participants received subcutaneous ustekinumab at weeks 0 and 4 (45 mg per dose for those ≤100 kg; 90 mg per dose for those >100 kg). Participants randomized to the abatacept group at week 12 received subcutaneous abatacept, 125 mg weekly, from weeks 12 to 39 and ustekinumab placebo at weeks 16 and 28. Participants randomized to the ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of participants with psoriasis relapse (loss of ≥50% of the initial Psoriasis Area and Severity Index improvement) between weeks 12 and 88. Secondary end points included time to psoriasis relapse, proportion of participants with psoriasis relapse between weeks 12 and 40, and adverse events. The psoriasis transcriptome and serum cytokines were evaluated. RESULTS: A total of 108 participants (mean [SD] age, 46.1 [12.1] years; 73 [67.6%] men) were treated with open-label ustekinumab; 91 were randomized to blinded treatment. Similar proportions of participants in the abatacept group and the ustekinumab group relapsed between weeks 12 and 88 (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41). Median time to relapse from the last dose of ustekinumab was similar between groups as well: 36 weeks (95% CI, 36-48 weeks) in the abatacept group vs 32 weeks (95% CI, 28-40 weeks) in the ustekinumab group. Similar numbers and rates of adverse events occurred. Abatacept did not maintain suppression of the pathogenic IL-23-mediated psoriasis molecular signature in lesions after ustekinumab withdrawal, and serum IL-19 levels increased. CONCLUSIONS AND RELEVANCE: This parallel-design, double-blind randomized clinical trial found that abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal because it did not completely block the pathogenic psoriasis molecular pathways that led to relapse. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01999868.