Safety and Danger Considerations of Novel Treatments for Atopic Dermatitis in Context of Primary Cutaneous Lymphomas

Abstract

The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination.

Keywords: JAK-STAT pathway; Sézary syndrome; atopic dermatitis; biologic treatment; cutaneous lymphoma; cytokine; interleukins; mycosis fungoides; small molecule inhibitors; tumor microenvironment.

Figure 1

The influence of agents targeting interleukins (IL) 4, 13, 22, and 31 and JAK/STAT pathways on the primary cutaneous lymphomas (PCLs) cells and tumorous microenvironment. The up and down arrows stand for increase/decrease of the interleukins concentration, cell count or receptor’s upregulation. IL-12 promotes phosphorylation of STAT4, thereby stimulating the cytotoxic mediated CD8(+) answer. Concomitantly, IL-4, IL-13, and IL-31 contribute to forming the Th-2 cytokine profile, which results in decreased cytotoxic immunosurveillance and lymphomagenesis. IL-4, IL-13, and IL-22 activate different Janus kinases, which promote the STAT3, STAT5, and STAT6 activation contributing to the transcription of pro-tumorous factors. In the advanced stages of the disease, this phenomenon may be seen more prominently. By blocking several pathways or cytokines, biologic drugs and small molecule inhibitors may affect both the malignant microenvironment and pathways in the PCLs cells.