Publications by authors named "Emanual Maverakis"

148 Publications

New Frontiers in Psoriatic Disease Research, Part I: Genetics, Environmental Triggers, Immunology, Pathophysiology, and Precision Medicine.

J Invest Dermatol 2021 Jul 21. Epub 2021 Jul 21.

UCSF Department of Dermatology, University of California San Francisco, San Francisco, California, USA. Electronic address:

Psoriasis is a chronic inflammatory condition characterized by systemic immune dysregulation. Over the past several years, advances in genetics, microbiology, immunology, and mouse models have revealed the complex interplay between the heritable and microenvironmental factors that drive the development of psoriatic inflammation. In the first of this two-part review series, the authors will discuss the newest insights into the pathogenesis of psoriatic disease and highlight how the evolution of these scientific fields has paved the way for a more personalized approach to psoriatic disease treatment.
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http://dx.doi.org/10.1016/j.jid.2021.02.764DOI Listing
July 2021

Reply to "Benralizumab: A potential tailored treatment for life-threatening DRESS in the COVID-19 era".

J Allergy Clin Immunol Pract 2021 Jul 15. Epub 2021 Jul 15.

Faculty of Medicine, University of Zurich, Zurich, Switzerland; Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; Christine Kühne Center for Allergy Research and Education CK-CARE, Davos, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2021.06.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299284PMC
July 2021

A Comparison of Expanded Human Regulatory T Cells Using Allogeneic Stimulated B Cells or Monocyte-Derived Dendritic Cells.

Front Immunol 2021 18;12:679675. Epub 2021 Jun 18.

Department of Surgery, University of California San Francisco, San Francisco, CA, United States.

Alloreactive regulatory T cells (arTregs) are more potent than polyclonal Tregs at suppressing immune responses to transplant antigens. Human arTregs can be expanded with allogeneic CD40L-stimulated B cells (sBcs) or stimulated-matured monocyte-derived dendritic cells (sDCs). Here, we compared the expansion efficiency and properties of arTregs stimulated using these two types of antigen-presenting cells. Compared to sBcs, sDCs stimulated Tregs to expand two times more in number. The superior expansion-inducing capacity of sDCs correlated with their higher expression of CD80, CD86, and T cell-attracting chemokines. sBc- and sDC-arTregs expressed comparable levels of FOXP3, HELIOS, CD25, CD27, and CD62L, demethylated FOXP3 enhancer and suppressive function. sBc- and sDCs-arTregs had similar gene expression profiles that were distinct from primary Tregs. sBc- and sDC-arTregs exhibited similar low frequencies of IFN-γ, IL-4, and IL-17A-producing cells, and the cytokine-producing arTregs expressed high levels of FOXP3. Almost all sBc- and sDC-arTregs expressed CXCR3, which may enable them traffic to inflammatory sites. Thus, sDCs-arTregs that expand more readily, are phenotypically similar to sBc-arTregs, supporting sDCs as a viable alternative for arTreg production for clinical evaluation.
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http://dx.doi.org/10.3389/fimmu.2021.679675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253048PMC
June 2021

Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID-19 patients.

Allergy 2021 Jun 22. Epub 2021 Jun 22.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Background: Coronavirus disease-2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID-19 may impact the development of the MDR.

Methods: Blood and skin samples from COVID-19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID-MDR), healthy controls, non-COVID-19-related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high-throughput multiplexed proteomic profiling of serum were performed.

Results: IMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8 T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID-MDR. The RNA sequencing transcriptome demonstrated a more robust cytotoxic response in COVID-MDR skin. However, severe acute respiratory syndrome coronavirus 2 was not detected in skin biopsies at the time point of MDR diagnosis. Serum proteomic profiling of COVID-MDR patients revealed upregulation of various inflammatory mediators (IL-4, IL-5, IL-6, TNF, and IFN-γ), eosinophil and Mo/Mac -attracting chemokines (MCP-2, MCP-3, MCP-4 and CCL11). Proteomics analyses demonstrated a massive systemic cytokine storm in COVID-MDR compared with the relatively milder cytokine storm observed in DRESS, while MDR did not exhibit such features.

Conclusion: A systemic cytokine storm may promote activation of Mo/Mac and cytotoxic CD8 T cells in severe COVID-19 patients, which in turn may impact the development of MDR.
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http://dx.doi.org/10.1111/all.14983DOI Listing
June 2021

Anti-Interleukin 23-Based Therapies May Shift Cutaneous Immune Responses: A Case of New-Onset Contact Dermatitis to Carbamates After Guselkumab for Psoriasis.

Dermatitis 2021 Jun 14. Epub 2021 Jun 14.

From the Department of Dermatology School of Medicine, University of California, Davis, Sacramento Department of Dermatology, Stanford University, Palo Alto Department of Pathology, University of California, Davis, Sacramento Dermatology Division, VA Northern California Health Care System, Mather.

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http://dx.doi.org/10.1097/DER.0000000000000765DOI Listing
June 2021

Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris.

N Engl J Med 2021 06 19;384(24):2295-2305. Epub 2021 May 19.

From the Perelman School of Medicine, University of Pennsylvania, and the Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia (V.P.W.); the Department of Dermatology, Rouen University Hospital and INSERM 1234, Normandie Université, Rouen (P.J.), and the Department of Dermatology, Groupe Hospitalier Paris Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris and INSERM Unité Mixte de Recherche 1125, Bobigny (F.C.) - all in France; the Sackler School of Medicine, Tel Aviv University, Tel Aviv, and Rabin Medical Center, Petah Tikva - both in Israel (D.M.); the Department of Dermatology, University of California, Davis, School of Medicine, Sacramento (E.M.), and Genentech, South San Francisco (A.K., D.M.C.) - both in California; Roche Products, Welwyn Garden City, United Kingdom (P.L.); F. Hoffmann-La Roche, Basel, Switzerland (L.G.); and Roche Products, Mississauga, ON, Canada (P.P.).

Background: Rituximab and mycophenolate mofetil are used to treat pemphigus vulgaris, but they have not been adequately compared in clinical trials.

Methods: In a randomized, controlled trial, we assigned patients with moderate-to-severe pemphigus vulgaris in a 1:1 ratio to receive intravenous rituximab (1000 mg on days 1, 15, 168, and 182) or oral mycophenolate mofetil (2 g per day), in addition to an oral glucocorticoid administered on the same tapering schedule in the two groups. The primary end point was sustained complete remission at week 52, defined as the healing of lesions with no new active lesions, as reflected by a Pemphigus Disease Area Index (PDAI) activity score of 0 (on a scale of 0 to 250, with higher scores indicating greater disease severity), for at least 16 weeks without the use of glucocorticoids. Secondary end points were the cumulative dose of glucocorticoids, the number of disease flares, and the change from baseline in the score on the Dermatology Life Quality Index (DLQI; scores range from 0 to 30, with higher scores indicating greater impairment).

Results: Of the 135 patients who underwent randomization, 67 were assigned to receive rituximab and 68 to receive mycophenolate mofetil. The primary outcome was assessed in the modified intention-to-treat population: 62 patients in the rituximab group and 63 in the mycophenolate mofetil group. The median PDAI activity scores at baseline were 22.7 in the rituximab group and 18.3 in the mycophenolate mofetil group. At week 52, sustained complete remission was observed in 25 patients (40%) in the rituximab group and in 6 (10%) in the mycophenolate mofetil group (difference, 31 percentage points; 95% confidence interval [CI], 15 to 45; P<0.001). The mean cumulative glucocorticoid dose during the 52-week treatment period was 3545 mg in the rituximab group and 5140 mg in the mycophenolate mofetil group (difference, -1595 mg; 95% CI, -2838 to -353; P<0.001). There were 6 disease flares in the rituximab group and 44 in the mycophenolate mofetil group (adjusted rate ratio, 0.12; 95% CI, 0.05 to 0.29; P<0.001). The mean change in DLQI score was -8.87 points and -6.00 points, respectively (difference, -2.87 points; 95% CI, -4.58 to -1.17; P = 0.001). Serious adverse events occurred in 15 of 67 patients (22%) in the rituximab group and in 10 of 68 (15%) in the mycophenolate mofetil group.

Conclusions: Rituximab was superior to mycophenolate mofetil in producing sustained complete remission at 52 weeks in patients with pemphigus vulgaris. Rituximab resulted in a greater reduction in glucocorticoid use than mycophenolate mofetil, but more patients in the rituximab group had serious adverse events. Further trials are needed to determine the comparative efficacy and safety of rituximab and mycophenolate mofetil beyond 52 weeks of treatment. (Funded by F. Hoffmann-La Roche; PEMPHIX ClinicalTrials.gov number, NCT02383589.).
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http://dx.doi.org/10.1056/NEJMoa2028564DOI Listing
June 2021

Long-term Follow-up and Correlative Analysis of Two Phase II Trials of Rituximab and Lenalidomide Followed by Continuous Lenalidomide in Untreated and Relapsed/Refractory Indolent Lymphoma.

Clin Cancer Res 2021 Jun 4. Epub 2021 Jun 4.

University of California, Davis, Department of Dermatology, Sacramento, California.

Purpose: Rituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described.

Patients And Methods: We conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies.

Results: At a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4-140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B (GranB) CD8 T cells and long-term complete response (LTCR; = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB CD8 T-cell levels (% total lymphocytes).

Conclusions: Rituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB CD8 T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4622DOI Listing
June 2021

IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses.

J Invest Dermatol 2021 Apr 15. Epub 2021 Apr 15.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.
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http://dx.doi.org/10.1016/j.jid.2021.03.019DOI Listing
April 2021

Transcriptome analysis of human dermal fibroblasts following red light phototherapy.

Sci Rep 2021 Apr 1;11(1):7315. Epub 2021 Apr 1.

Department of Dermatology, University of California at Davis, Sacramento, CA, USA.

Fibrosis occurs when collagen deposition and fibroblast proliferation replace healthy tissue. Red light (RL) may improve skin fibrosis via photobiomodulation, the process by which photosensitive chromophores in cells absorb visible or near-infrared light and undergo photophysical reactions. Our previous research demonstrated that high fluence RL reduces fibroblast proliferation, collagen deposition, and migration. Despite the identification of several cellular mechanisms underpinning RL phototherapy, little is known about the transcriptional changes that lead to anti-fibrotic cellular responses. Herein, RNA sequencing was performed on human dermal fibroblasts treated with RL phototherapy. Pathway enrichment and transcription factor analysis revealed regulation of extracellular matrices, proliferation, and cellular responses to oxygen-containing compounds following RL phototherapy. Specifically, RL phototherapy increased the expression of MMP1, which codes for matrix metalloproteinase-1 (MMP-1) and is responsible for remodeling extracellular collagen. Differential regulation of MMP1 was confirmed with RT-qPCR and ELISA. Additionally, RL upregulated PRSS35, which has not been previously associated with skin activity, but has known anti-fibrotic functions. Our results suggest that RL may benefit patients by altering fibrotic gene expression.
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http://dx.doi.org/10.1038/s41598-021-86623-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017006PMC
April 2021

Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease.

J Clin Invest 2021 Mar;131(5)

Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California, USA.

IgE induced by type 2 immune responses in atopic dermatitis is implicated in the progression of atopic dermatitis to other allergic diseases, including food allergies, allergic rhinitis, and asthma. However, the keratinocyte-derived signals that promote IgE and ensuing allergic diseases remain unclear. Herein, in a mouse model of atopic dermatitis-like skin inflammation induced by epicutaneous Staphylococcus aureus exposure, keratinocyte release of IL‑36α along with IL-4 triggered B cell IgE class-switching, plasma cell differentiation, and increased serum IgE levels-all of which were abrogated in IL-36R-deficient mice or anti-IL‑36R-blocking antibody-treated mice. Moreover, skin allergen sensitization during S. aureus epicutaneous exposure-induced IL-36 responses was required for the development of allergen-specific lung inflammation. In translating these findings, elevated IL‑36 cytokines in human atopic dermatitis skin and in IL‑36 receptor antagonist-deficiency patients coincided with increased serum IgE levels. Collectively, keratinocyte-initiated IL‑36 responses represent a key mechanism and potential therapeutic target against allergic diseases.
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http://dx.doi.org/10.1172/JCI143334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919715PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Baricitinib in patients with moderate-to-severe atopic dermatitis: Results from a randomized monotherapy phase 3 trial in the United States and Canada (BREEZE-AD5).

J Am Acad Dermatol 2021 Jul 16;85(1):62-70. Epub 2021 Feb 16.

K Papp Clinical Research and Probity Medical Research, Waterloo, Ontario, Canada.

Background: Baricitinib, an oral selective Janus kinase 1/Janus kinase 2 inhibitor, is being studied for moderate-to-severe atopic dermatitis (AD) in adults.

Objective: To evaluate the efficacy and safety of baricitinib monotherapy in a North American phase 3 trial (BREEZE-AD5/NCT03435081) of adults with moderate-to-severe AD who responded inadequately or were intolerant to topical therapy.

Methods: Patients (N = 440) were randomized 1:1:1 to once-daily placebo or baricitinib (1 mg or 2 mg). The primary endpoint was the proportion of patients achieving ≥75% reduction in the Eczema Area and Severity Index at week 16. A key secondary endpoint was the proportion of patients achieving a validated Investigator Global Assessment for AD score of 0 (clear)/1(almost clear) with ≥2-point improvement.

Results: At week 16, the proportion of patients achieving Eczema Area and Severity Index was 8%, 13%, and 30% (P < .001, 2 mg vs placebo) and those with a validated Investigator Global Assessment for AD score of 0/1 were 5%, 13%, and 24% (P < .001, 2 mg vs placebo) for placebo, baricitinib 1 mg, and baricitinib 2 mg, respectively. Safety findings were similar to those of other baricitinib AD studies.

Limitations: Short-term clinical trial results may not be generalizable to real-world settings.

Conclusion: Baricitinib was efficacious for patients with moderate-to-severe AD with no new safety findings over 16 weeks.
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http://dx.doi.org/10.1016/j.jaad.2021.02.028DOI Listing
July 2021

Soluble CD40L activates soluble and cell-surface integrin αvβ3, α5β1, and α4β1 by binding to the allosteric ligand-binding site (site 2).

J Biol Chem 2021 Jan-Jun;296:100399. Epub 2021 Feb 9.

Department of Dermatology, UC Davis School of Medicine, Sacramento, California, USA; Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, California, USA. Electronic address:

CD40L is a member of the TNF superfamily that participates in immune cell activation. It binds to and signals through several integrins, including αvβ3 and α5β1, which bind to the trimeric interface of CD40L. We previously showed that several integrin ligands can bind to the allosteric site (site 2), which is distinct from the classical ligand-binding site (site 1), raising the question of if CD40L activates integrins. In our explorations of this question, we determined that integrin α4β1, which is prevalently expressed on the same CD4+ T cells as CD40L, is another receptor for CD40L. Soluble (s)CD40L activated soluble integrins αvβ3, α5β1, and α4β1 in cell-free conditions, indicating that this activation does not require inside-out signaling. Moreover, sCD40L activated cell-surface integrins in CHO cells that do not express CD40. To learn more about the mechanism of binding, we determined that sCD40L bound to a cyclic peptide from site 2. Docking simulations predicted that the residues of CD40L that bind to site 2 are located outside of the CD40L trimer interface, at a site where four HIGM1 (hyper-IgM syndrome type 1) mutations are clustered. We tested the effect of these mutations, finding that the K143T and G144E mutants were the most defective in integrin activation, providing support that this region interacts with site 2. We propose that allosteric integrin activation by CD40L also plays a role in CD40L signaling, and defective site 2 binding may be related to the impaired CD40L signaling functions of these HIGM1 mutants.
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http://dx.doi.org/10.1016/j.jbc.2021.100399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960543PMC
February 2021

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer.

Clin Cancer Res 2021 May 10;27(9):2470-2480. Epub 2021 Feb 10.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade.

Patients And Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink.

Results: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3-5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8 and CD8/PD-1/Ki-67 T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood.

Conclusions: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102320PMC
May 2021

Porphyria cutanea tarda presenting as a lichenoid eruption.

Photodermatol Photoimmunol Photomed 2021 May 22;37(3):233-235. Epub 2020 Dec 22.

Department of Dermatology, University of California, Davis, Sacramento, CA, USA.

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http://dx.doi.org/10.1111/phpp.12640DOI Listing
May 2021

Obesity induces gut microbiota alterations and augments acute graft-versus-host disease after allogeneic stem cell transplantation.

Sci Transl Med 2020 11;12(571)

Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.

The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by acute and chronic graft-versus-host disease (GVHD). The impact of obesity on allo-HSCT outcomes is poorly understood. Here, we report that obesity had a negative and selective impact on acute gut GVHD after allo-HSCT in mice with diet-induced obesity (DIO). These animals exhibited increased gut permeability, endotoxin translocation across the gut, and radiation-induced gastrointestinal damage after allo-HSCT. After allo-HSCT, both male and female DIO mouse recipients showed increased proinflammatory cytokine production and expression of the GVHD marker ST2 (IL-33R) and MHC class II molecules; they also exhibited decreased survival associated with acute severe gut GVHD. This rapid-onset, obesity-associated gut GVHD depended on donor CD4 T cells and occurred even with a minor MHC mismatch between donor and recipient animals. Retrospective analysis of clinical cohorts receiving allo-HSCT transplants from unrelated donors revealed that recipients with a high body mass index (BMI, >30) had reduced survival and higher serum ST2 concentrations compared with nonobese transplant recipients. Assessment of both DIO mice and allo-HSCT recipients with a high BMI revealed reduced gut microbiota diversity and decreased Clostridiaceae abundance. Prophylactic antibiotic treatment protected DIO mouse recipients from endotoxin translocation across the gut and increased inflammatory cytokine production, as well as gut pathology and mortality, but did not protect against later development of chronic skin GVHD. These results suggest that obesity-induced alterations of the gut microbiota may affect GVHD after allo-HSCT in DIO mice, which could be ameliorated by prophylactic antibiotic treatment.
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http://dx.doi.org/10.1126/scitranslmed.aay7713DOI Listing
November 2020

A site-specific map of the human plasma glycome and its age and gender-associated alterations.

Sci Rep 2020 10 15;10(1):17505. Epub 2020 Oct 15.

Department of Dermatology, University of California Davis School of Medicine, 3301 C Street Suite 1400, Sacramento, CA, 95816, USA.

Alterations in the human glycome have been associated with cancer and autoimmunity. Thus, constructing a site-specific map of the human glycome for biomarker research and discovery has been a highly sought-after objective. However, due to analytical barriers, comprehensive site-specific glycoprofiling is difficult to perform. To develop a platform to detect easily quantifiable, site-specific, disease-associated glycan alterations for clinical applications, we have adapted the multiple reaction monitoring mass spectrometry method for use in glycan biomarker research. The adaptations allow for highly precise site-specific glycan monitoring with minimum sample prep. Using this technique, we successfully mapped out the relative abundances of the most common 159 glycopeptides in the plasma of 97 healthy volunteers. This plasma glycome map revealed 796 significant (FDR < 0.05) site-specific inter-protein and intra-protein glycan associations, of which the vast majority were previously unknown. Since age and gender are relevant covariants in biomarker research, these variables were also characterized. 13 glycopeptides were found to be associated with gender and 41 to be associated with age. Using just five age-associated glycopeptides, a highly accurate age prediction model was constructed and validated (r = 0.62 ± 0.12). The human plasma site-specific glycan map described herein has utility in applications ranging from glycan biomarker research and discovery to the development of novel glycan-altering interventions.
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http://dx.doi.org/10.1038/s41598-020-73588-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567094PMC
October 2020

Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.

The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.
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http://dx.doi.org/10.1172/jci.insight.142067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605526PMC
October 2020

Benralizumab for severe DRESS in two COVID-19 patients.

J Allergy Clin Immunol Pract 2021 01 8;9(1):481-483.e2. Epub 2020 Oct 8.

Faculty of Medicine, University of Zurich, Zurich, Switzerland; Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; Department of Dermatology, Hochgebirgsklinik Davos, Davos, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.09.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543785PMC
January 2021

Pyoderma gangrenosum.

Nat Rev Dis Primers 2020 10 8;6(1):81. Epub 2020 Oct 8.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that presents with rapidly developing, painful skin ulcers hallmarked by undermined borders and peripheral erythema. Epidemiological studies indicate that the average age of PG onset is in the mid-40s, with an incidence of a few cases per million person-years. PG is often associated with a variety of other immune-mediated diseases, most commonly inflammatory bowel disease and rheumatoid arthritis. The cause of PG is not well understood, but PG is generally considered an autoinflammatory disorder. Studies have focused on the role of T cells, especially at the wound margin; these cells may support the destructive autoinflammatory response by the innate immune system. PG is difficult to diagnose as several differential diagnoses are possible; in addition to clinical examination, laboratory tests of biopsied wound tissue are required for an accurate diagnosis, and new validated diagnostic criteria will facilitate the process. Treatment of PG typically starts with fast-acting immunosuppressive drugs (corticosteroids and/or cyclosporine) to reduce inflammation followed by the addition of more slowly acting immunosuppressive drugs with superior adverse event profiles, including biologics (in particular, anti-tumour necrosis factor (TNF) agents). Appropriate wound care is also essential. Future research should focus on PG-specific outcome measures and PG quality-of-life studies.
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http://dx.doi.org/10.1038/s41572-020-0213-xDOI Listing
October 2020

Osteonecrosis of the calvarium: When clear margins are an impractical goal.

Dermatol Ther 2020 11 15;33(6):e14278. Epub 2020 Sep 15.

Department of Dermatology, University of California, Davis, Sacramento, California, USA.

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http://dx.doi.org/10.1111/dth.14278DOI Listing
November 2020

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.

JCI Insight 2020 10 2;5(19). Epub 2020 Oct 2.

Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.
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http://dx.doi.org/10.1172/jci.insight.139930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566715PMC
October 2020

"Autoinflammatory psoriasis"-genetics and biology of pustular psoriasis.

Cell Mol Immunol 2021 02 19;18(2):307-317. Epub 2020 Aug 19.

Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.
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http://dx.doi.org/10.1038/s41423-020-0519-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027616PMC
February 2021

The cutaneous and intestinal microbiome in psoriatic disease.

Clin Immunol 2020 09 15;218:108537. Epub 2020 Jul 15.

Department of Dermatology, University of California, Davis, Sacramento, CA, United States. Electronic address:

Psoriasis (PsO) and psoriatic arthritis (PsA) are chronic immune-mediated inflammatory diseases of multifactorial etiology. In addition to genetic and environmental factors, evidence supports involvement of a dysregulated human microbiome in the pathogenesis of psoriatic disease. In particular, alterations in the composition of the microbiome, termed dysbiosis, can result in downstream proinflammatory effects in the gut, skin, and joints. Both the cutaneous and intestinal microbial populations are implicated in the pathogenesis of psoriatic disease, although exact mechanisms are unclear. Herein, we review the relationship between the human microbiome and psoriatic disease. Further insight into the functions of the microbiome may allow for greater understanding of inflammatory disease processes and identification of additional therapeutic targets.
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http://dx.doi.org/10.1016/j.clim.2020.108537DOI Listing
September 2020

Incidence, Clinical Features, Management, and Prevention of Herpes Zoster in Patients Receiving Antitumor Necrosis Factor Therapy: A Clinical Review.

J Cutan Med Surg 2020 May/Jun;24(3):278-284. Epub 2020 Apr 2.

156053 VA Medical Center Sacramento, Division of Rheumatology & Immunology, Mather, CA, USA.

Tumor necrosis factor (TNF) inhibitors have been used as an excellent therapeutic option in a variety of chronic inflammatory conditions. However, a recognized significant adverse effect of TNF inhibitor therapy is the increased risk of infections. The influence of TNF inhibitors on the course of coexisting or newly developed viral infections has not been extensively investigated. Therefore, we reviewed the recent publications to highlight the incidence, clinical features, management, and prevention of herpes zoster in patients who are receiving TNF inhibitors.
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http://dx.doi.org/10.1177/1203475420914622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238506PMC
February 2021

Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans.

Proc Natl Acad Sci U S A 2020 04 25;117(14):7633-7644. Epub 2020 Mar 25.

Department of Chemistry, University of California, Davis, CA 95616.

Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi α-mannosidase I coding gene , leading to elevation of extended high-mannose glycans with terminating α-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting α-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that α-1,2-mannosylated -glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis.
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http://dx.doi.org/10.1073/pnas.1916498117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148571PMC
April 2020

Targeted Treatment for Erythrodermic Psoriasis: Rationale and Recent Advances.

Drugs 2020 Apr;80(6):525-534

Department of Dermatology, University of Michigan, Ann Arbor, MI, 48109, USA.

Erythrodermic psoriasis (EP) is an extreme and often refractory variant of psoriasis with high morbidity and increased mortality, and is frequently classified as a dermatological emergency. The pathophysiology of EP is largely unknown but is thought to differ from that of plaque psoriasis. Treatment of EP is challenging, and usually based on clinical experience and patient co-morbidities, due to its low incidence and limited clinical evidence. Conventional treatments, such as topical glucocorticoid therapy, cyclosporin, acitretin, and methotrexate have some but limited efficacy in EP, and treatment discontinuation may result in flares. Newer biological drugs, including anti-TNF, anti-IL-17, and anti-IL-12/23 agents, have shown promise in therapeutic management of EP, but most of the available evidence is currently based on small case series and reports. Few studies have compared available treatment options for EP, and further clinical studies are necessary to provide clinical data and optimal treatment guidelines for EP patients. Here, we provide a comprehensive review of the background of EP, assess the available clinical data on the efficacy of targeted therapies, and aim to provide a foundation for clinical decision making for this rare form of psoriasis.
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http://dx.doi.org/10.1007/s40265-020-01283-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167352PMC
April 2020

Successful Management of Anti-TNF-Induced Psoriasis Despite Continuation of Therapy in a Pyoderma Gangrenosum Patient

J Drugs Dermatol 2020 Feb;19(2):199-201

Pyoderma gangrenosum is an inflammatory, neutrophil-mediated disorder that is difficult to treat. Tumor necrosis factor and other inflammatory mediators are among the most promising therapeutic targets. We present a case of a 60-year-old woman with recalcitrant pyoderma gangrenosum treated with adalimumab, who paradoxically developed psoriasis. Secukinumab, an interleukin-17 inhibitor, was added to her regimen, resulting in successful treatment of her psoriasis. Secukinumab was later replaced by methotrexate, resulting in remission of both pyoderma gangrenosum and maintenance of a psoriasis-free state. We conclude that paradoxically induced psoriatic lesions can resolve with adjunct therapy despite continuation of anti-tumor necrosis factor agents. J Drugs Dermatol. 2020;19(2)199-201. doi:10.36849/JDD.2020.4662
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http://dx.doi.org/10.36849/JDD.2020.4662DOI Listing
February 2020

Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses.

J Allergy Clin Immunol 2020 05 28;145(5):1406-1415. Epub 2019 Dec 28.

Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Background: Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity.

Objectives: We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD.

Methods: We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings.

Results: Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, T1, T2, and T17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of T1, T2, and T17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator.

Conclusions: Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened T2, T1, T17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.
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http://dx.doi.org/10.1016/j.jaci.2019.11.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214216PMC
May 2020

Non-surgical management of primary invasive melanoma.

J Dermatolog Treat 2019 Nov 20:1-4. Epub 2019 Nov 20.

Department of Surgery, UC Davis School of Medicine, Sacramento, CA, USA.

Surgical excision is standard-of-care for primary invasive melanoma, but best care can be unclear for patients who are surgically high-risk or for whom resection may be excessively morbid. Alternatives to surgical excision have emerged for treatment of metastatic melanoma but have not yet been explored for primary invasive melanoma. Two elderly patients with primary invasive melanoma with many medical co-morbidities who were not surgical candidates were determined to be appropriate candidates for an intralesional IL-2 based regimen. Herein we report their clinical and histological outcome. An intralesional-based regimen (intralesional IL-2, topical imiquimod cream 5%, and tretinoin cream 0.1% under occlusion to the treatment site) was administered over the course of six to seven weeks, followed by two weeks of topical-only therapy. A complete response was seen after eight to nine weeks of treating invasive melanomas that were ≥1.85 mm and 5.5 mm thick. For patients with primary invasive melanoma on high morbidity sites and patients who are poor surgical candidates, a neoadjuvant intralesional IL-2-based approach may be a reasonable alternative. The two cases presented here suggest that alternative intralesional-based treatment modalities may minimize the size of the excision site and can be associated with complete histological clearance of invasive melanoma.
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http://dx.doi.org/10.1080/09546634.2019.1687830DOI Listing
November 2019
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