Real-life use of apremilast for the treatment of psoriasis in patients with oncological comorbidities: a retrospective descriptive multicentre study in France.

BACKGROUND: Systemic treatment options for psoriasis are limited for patients with recent neoplasia. OBJECTIVES: We report the real-life use of apremilast (APR) in patients with psoriasis and recent cancer. MATERIALS & METHODS: We conducted a retrospective, multicentre study in five hospitals and among 120 private dermatologists in the north of France from January 2015 to May 2021. We included patients treated with APR for psoriasis and suffering from an active cancer or who had been diagnosed with a cancer or treated for a cancer within the last five years. RESULTS: We included 23 patients diagnosed with a cancer, on average 2.6 years before the introduction of APR for psoriasis. In most patients, APR was specifically chosen due to oncological history. At 16±8 weeks, 55% (n=11/20) of patients had achieved PASI 50 score, 30% (n=6/20) PASI 75, 5% (n=3/20) PASI 90 and 37.5% (n=3/8) of them had a significant improvement in quality of life. Non-serious adverse events were observed in 65.2% (n=15/23) of patients (diarrhoea in 39%), resulting in discontinuation of treatment for 27.8%. The average duration of treatment was 303.8±252.4 days. For four patients, a recurrence or a progression of cancer was recorded during APR treatment. CONCLUSION: In our patients with both psoriasis and cancer, APR improved quality of life, with a good safety profile. A larger study, matched for type, stage and treatment of underlying cancer, would be necessary to draw further conclusions about the oncological safety of APR.

Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR.

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

Keratinocyte Expression of A20/TNFAIP3 Controls Skin Inflammation Associated with Atopic Dermatitis and Psoriasis.

Keratinocytes are key players in chronic inflammatory skin diseases. A20 regulates NF-κB-dependent expression of proinflammatory genes and cell death, but the impact of its expression in keratinocytes on systemic inflammation and skin disorders has not been determined. Comparative transcriptomic analysis of microdissected epidermis showed that A20 is down-regulated in involved epidermis, but not in dermis, of psoriasis and atopic dermatitis patients, suggesting that loss of A20 expression in keratinocytes increases the vulnerability for psoriasis/atopic dermatitis induction. We have previously shown that epidermis-specific A20 knockout mice (A20EKO) develop mild epidermal hyperplasia but no macroscopic skin inflammation. We now show that various cytokines and chemokines are up-regulated in A20EKO mouse skin. A20EKO mice also display systemic proinflammatory changes, even in the absence of skin immune cell infiltration, and an exacerbated disease severity upon induction of experimental psoriasis, atopic dermatitis, or skin barrier disruption. Keratinocytes showed increased proinflammatory gene expression in the absence of A20 in unstimulated and IL-17A-stimulated conditions, in part resulting from uncontrolled MyD88-dependent signaling. Our findings indicate that absence of A20 in keratinocytes leads to systemic inflammation at homeostatic conditions and is sufficient to exacerbate inflammatory skin disorders associated with different immune profiles by increasing cytokine and chemokine expression.

Hemophagocytic lymphohistiocytosis in patients with metastatic malignant melanoma.

Hemophagocytic lymphohistiocytosis (HLH) is an autoinflammatory disease that classically occurs because of infections, autoinflammatory, or autoimmune diseases, hematologic cancers, and rarely because of solid tumor. We report a rare case of HLH attributed to metastatic malignant melanoma treated without corticosteroid and with a nonfatal outcome thanks to specific therapies: etoposide for HLH and a selective inhibitor of mutated forms of BRAF kinase associated with a MEK inhibitor for melanoma.

Extensive Necrotic Purpura in Levamisole-Adulterated Cocaine Abuse - A Case Report.

Levamisole, which is used as an adulterated compound of cocaine, is currently being seen year after year in cocaine intoxication. For a few cases in the last decade, necrotic purpura and neutropenia after levamisole/cocaine intoxication have been described in the medical community. Herein, we present an original case of levamisole intoxication of a 40-year-old woman who smoked heroin and cocaine few during a month. She rapidly presented an extensive necrotic purpura of the nose, cheeks and extremities (lower and upper), and immunologic reactions (positive anti-MPO and anti-HNE). Levamisole was detected on hairs with ultra-high performance liquid chromatography and tandem mass spectrometry. The case reports also a probable cocaine supplier deceit, which bring pure drug for hospital investigation after the intoxication of his client. The intoxicated woman had survived with several skin and chronic pain complications. That case recalls the knowledge about levamisole with a short review of the forensic literature.