Blocking IL-6 Pathway May Prevent Progression of Skin Ulcers in Calciphylaxis CKD-Related Disease

Research published in Science Translational Medicine discovered that a novel biological pathway, known as the IL6 pathway, is central to the skin lesion initiation and progression. The authors believe that by blocking this pathway, it is likely that skin ulcers resulting from a chronic kidney disease (CKD)-related condition, calciphylaxis, can be prevented and pain resolved.^1,2

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The overall global burden of CKD is rising, according to the investigators, with over 800 million people worldwide being affected by the disease. Vascular diseases in patients with CKD are unique and often grouped as uremic vascular diseases. A notable CKD-related condition is calciphylaxis, which is characterized by severe and painful skin ulcers, otherwise known as dermal microvessel thrombosis, that inflict painful cutaneous necrosis and currently have no known cure. It is most common in patients who have end-stage kidney disease.^1,2

The findings showed that the IL-6-tissue factor (TF)-inducing ability of calciphylaxis serum was an activity marker and IL-6 was a therapeutic target for uremic calciphylaxis. Specifically, in the study, the authors demonstrate that sera from patients with calciphylaxis induced de novo synthesis of IL-6 and soluble IL-6 receptor (IL-6R), stimulated Janus kinase-2 and signal transducer, as well as activator of transcription (STAT)–3 phosphorylation in primary human dermal microvascular endothelial cells (ECs).¹

In addition, the authors observed that calciphylaxis skin had an altered microenvironment that was characterized by a gain of proximal and distal IL-6 ligand-receptor interactions. Microvessels were shown to be the predominant senders and recipients of IL-6 signaling, and along with upregulated A disintegrin and metalloproteinase 17 in dermal vasculature and interstitial IL-6R, it supported trans–IL-6 signaling in calciphylaxis lesions.¹

“This study reveals the presence of a pathological and harmful cycle between the fat under the skin, sweat glands, and small blood vessels that keep feeding onto itself. If this cycle isn’t stopped and remains unchecked, it will lead to the skin ulcers that won’t heal. Using the specific pathway we identified, we could break this cycle and prevent the skin ulcers from getting worse,” corresponding author Vipul Chitalia, MD, PhD, professor of medicine, explained in a news release.²

Further, calciphylaxis serum up-regulated thymidine phosphorylase (TYMP) in ECs. Because TYMP upregulated IL-6, it then activated TF, which is a primary trigger of the extrinsic coagulation cascade. IL-6–TF signaling in ECs was partially triggered by elevated IL-6 and kynurenine amounts in calciphylaxis serum, and it was inhibited by anti–IL-6 treatment.¹

Additionally, TF-inducing ability of calciphylaxis serum was observed to be correlated with disease activity and response to IL-6 inhibitors in ECs. Therefore, calciphylaxis is a combination of serum-inducing TYMP–IL-6–TF signaling in ECs as well as a heterogeneous permissive local dermal microenvironment. The latter of which is characterized by microvessels that initiate IL-6 signaling and multiway crosstalk with adipocytes and eccrine glands, therefore extending the sinister thrombotic milieu.¹

“Those drugs are likely to prevent progression of the skin ulcers and resolve the pain that we see in patients with calciphylaxis. Human trials are now needed to show the benefit of those drugs,” concluded coauthor Jean Francis, MD, associate professor of medicine.²

REFERENCES

1. Napoleon MA, Yang X, Zhang Y, et al. Activation and targetability of TYMP–IL-6–TF signaling in the skin microenvironment in uremic calciphylaxis. Sci. Transl. Med. 2025;17(795):eadn5772. doi:10.1126/scitranslmed.adn5772

2. Boston University School of Medicine. Researchers identify pathway responsible for calciphylaxis, a rare and serious condition. News release. April 23, 2025. Accessed April 23, 2025. https://www.eurekalert.org/news-releases/1081463