Objective
To our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and ...chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA.
Methods
We conducted a comprehensive analysis of cytokine and chemokine activation and genes representative of the inflammatory processes in PsA. Paired PsA synovial tissue and skin samples were obtained from 12 patients on the same day. Gene expression studies were performed using Affymetrix HGU133 Plus 2.0 arrays. Confirmatory quantitative real‐time polymerase chain reaction (PCR) was performed on selected transcripts. Cell populations were assessed by immunohistochemistry and immunofluorescence.
Results
Globally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger interleukin‐17 (IL‐17) gene signature in skin than in synovium and more equivalent tumor necrosis factor (TNF) and interferon‐γ gene signatures in both tissues. These results were confirmed with real‐time PCR.
Conclusion
This is the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in PsA. Our results support clinical trial data showing that PsA skin and joint disease are similarly responsive to TNF antagonists, while IL‐17 antagonists have better results in PsA skin than in PsA joints. Genes selectively expressed in PsA synovium might direct future therapies for PsA.
IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease ...mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro.
Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes.
The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the "RHE" genes in psoriasis patients treated in vivo with this IL-17 antagonist.
Immune checkpoint inhibition (ICI) improves survival outcomes for patients with several types of cancer including metastatic melanoma (MM), but serious immune-related adverse events requiring ...intervention with immunosuppressive medications occur in a subset of patients. Skin toxicity (ST) has been reported to be associated with better response to ICI. However, understudied factors, such as ST severity and potential survivor bias, may influence the strength of these observed associations.
To examine the potential confounding impact of such variables, we analyzed advanced cancer patients enrolled prospectively in a clinicopathological database with protocol-driven follow up and treated with ICI. We tested the associations between developing ST, stratified as no (n = 617), mild (n = 191), and severe (n = 63), and progression-free survival (PFS) and overall survival (OS) in univariable and multivariable analyses. We defined severe ST as a skin event that required treatment with systemic corticosteroids. To account for the possibility of longer survival associating with adverse events instead of the reverse, we treated ST as a time-dependent covariate in an adjusted model.
Both mild and severe ST were significantly associated with improved PFS and OS (all P < 0.001). However, when adjusting for the time from treatment initiation to time of skin event, severe ST was not associated with PFS benefit both in univariable and multivariable analyses (P = 0.729 and P = 0.711, respectively). Receiving systemic steroids for ST did not lead to significant differences in PFS or OS compared to patients who did not receive systemic steroids.
Our data reveal the influence of time to event and its severity as covariates in analyzing the relationship between ST and ICI outcomes. These differences in outcomes cannot be solely explained by the use of immunosuppressive medications, and thus highlight the importance of host- and disease-intrinsic factors in determining ICI response and toxicity.
The patient data used in this manuscript come from patients who were prospectively enrolled in two institutional review board-approved databases at NYU Langone Health (institutional review board #10362 and #S16-00122).
BackgroundRecent research suggests that baseline body mass index (BMI) is associated with response to immunotherapy. In this study, we test the hypothesis that worsening nutritional status prior to ...the start of immunotherapy, rather than baseline BMI, negatively impacts immunotherapy response.MethodsWe studied 629 patients with advanced cancer who received immune checkpoint blockade at New York University. Patients had melanoma (n=268), lung cancer (n=128) or other primary malignancies (n=233). We tested the association between BMI changes prior to the start of treatment, baseline prognostic nutritional index (PNI), baseline BMI category and multiple clinical end points including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).ResultsDecreasing pretreatment BMI and low PNI were associated with worse BOR (p=0.04 and p=0.0004), ORR (p=0.01 and p=0.0005), DCR (p=0.01 and p<0.0001), PFS (p=0.02 and p=0.01) and OS (p<0.001 and p<0.001). Baseline BMI category was not significantly associated with any treatment outcomes.ConclusionStandard of care measures of worsening nutritional status more accurately associate with immunotherapy outcomes than static measurements of BMI. Future studies should focus on determining whether optimizing pretreatment nutritional status, a modifiable variable, leads to improvement in immunotherapy response.
In this report, we describe the case of a 28-year-old female with bilateral breast cancer in the setting of a BRCA1 mutation, who presented to dermatology with an eczematous reaction, ultimately ...diagnosed as a cutaneous immune-related adverse event (cirAE) secondary to an immune checkpoint inhibitor (ICI), pembrolizumab. Our case report highlights a novel therapeutic option for an eczematous cirAE: the topical JAK 1/2 inhibitor, ruxolitinib. CirAEs can occur in up to 55% of patients on ICIs, a class of medications seeing rapidly increasing use in cancer therapy, and prior research has demonstrated that ICI-induced dermatitis may involve different pathways than traditionally observed in their spontaneous counterparts. Specifically, marked Th1 skewing is noted in ICI-induced dermatitis, as opposed to a predominant Th2 response which typically characterizes spontaneous atopic dermatitis. To our knowledge, this is the first case report in the literature discussing use of a topical JAK inhibitor, ruxolitinib, in the treatment of topical steroid-refractory cirAEs. Furthermore, as topical JAK inhibitors are thought to not carry the risks of systemic JAK inhibitors, including malignancy, ruxolitinib cream is a promising therapeutic option for this challenging patient population.
Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received ...immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct.
We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010-2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5).
Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05).
AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.
Background
Provider opt-out of accepting Medicare insurance is a nationally tracked metric by the Centers for Medicare & Medicaid Services (CMS) for all physicians, including dermatologists. Although ...this usually only consists of a small number of providers, the magnitude of opting out has varied historically, often tracing changes in systemic health care policy.
Objective
In this paper, we explored dermatologist opt-out data since 2001, as reported by the CMS, to characterize trends and provide evidence that shifts in provider opt-out may represent a potential indicator of the state of health policy and possible needs for reform as it pertains to Medicare.
Methods
The publicly available Opt Out Affidavits data set, available from the CMS, was evaluated for providers in all dermatologic specialties from January 1, 2001, to May 27, 2022.
Results
There were a total of 196 dermatology opt-outs in the overall period, with the largest spike being 33 providers in 2016, followed by generally consistent decreases through 2021. In the most recent 12 months of data, the number of new monthly opt-outs from January 2022 to May 2022 was significantly higher than that of the trailing 7 months of 2021 (P=.03).
Conclusions
Despite decreasing numbers of dermatologist opt-outs in the late-2010s, 2022 was marked by a significant increase in opt-outs. The reduced acceptance of Medicare by dermatologists may present risks to care access, so it is important to frequently assess physician opt-out data and changes over time.
Immune checkpoint inhibitors (ICIs) such as pembrolizumab have revolutionized the treatment of advanced melanoma, but many patients do not respond to ICIs alone, and thus there is need for additional ...treatment options. Topical immunomodulators such as diphencyprone (DPCP) also have clinical use in advanced melanoma, particularly in the treatment of cutaneous metastases. In a previous report, we characterized the enhanced clinical response to dual agent immunotherapy with pembrolizumab and DPCP in a patient with cutaneous melanoma metastases. To improve mechanistic understanding of this response, we analyzed proteomic data using the Olink immuno-oncology panel of 96 biomarkers from tissue and serum samples of this patient throughout his treatment course. Particular attention was paid to programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) given they are all targeted by ICIs in clinical practice. These proteins were upregulated during the period of DPCP monotherapy, then downregulated during pembrolizumab monotherapy, and then robustly upregulated again during dual therapy. Although not exclusively, the induction of checkpoint inhibitor proteins in the presence of DPCP suggests potential synergy between this agent and ICIs in the treatment of cutaneous melanoma metastases. Large-scale investigation is warranted to further evaluate this potential novel combination therapeutic approach.
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