Hyaluronic Acid-Based Products Are Strictly Contraindicated in Scleroderma-Related Skin Ulcers

Giulio Gualdi, MD; Paola Monari, MD; Daniele Cammalleri, MD; Laura Pelizzari, MD; Piergiacomo Calzavara Pinton, PhD


Wounds. 2019;31(3):81-84. 

In This Article


At first glance, these results confirm that HA-based treatment modalities are effective in healing chronic skin wounds. But if the etiology of the ulcers is distinguished, it is clear and evident that inflammatory lesions worsened after topical application of HA. In particular, patients with scleroderma show an important and rapid inflammatory condition resulting in a net clinical deterioration using these HA-based products (92.7%), while in patients with noninflammatory ulcers, the severe inflammatory event is reduced to 1.5% with a recovery of 98.5%. Undoubtedly, HA is an important component of the ECM, playing a major role in the wound healing process; signals transduced by HA can regulate fundamental cellular function, including growth, adhesion, and cellular migration through specific receptors.[9] Its activity is supported by a large number of experimental and clinical studies in wound healing,[1] so that many companies invest in new topical formulations, associated or not with other active components, in order to assess the best topical product for the promotion or acceleration of reepithelization in superficial cutaneous ulcers.[10]

Hyaluronic acid in wound dressings has certainly helped to expand the therapeutic arsenal in the context of wound care, helping both the work of the physician as well as the healing process for the patient. However, like any innovation, HA must be placed in the right context. In particular, despite that new HA-based dressings do not have specific indications, clinicians must be aware that this glycosaminoglycan plays a role in the pathogenesis of some diseases. In particular, the correlation between HA and scleroderma is well known;[11] in fact, hyaluronic serum level is considered a good indicator of this disease's activity. In sclerodermic skin, there is a chronic inflammation that affects the connecting tissue and leads to progressive fibrosis of the tissue.[12] It is characterized by aberrations of ECM deposition, an alteration in the microvasculature, and an abnormal immunological response. Cultured fibroblasts from wounds in patients with scleroderma overproduce various ECM components, particularly hyaluronan, as well as collagen I, III, and VII and fibronectin.[13] Hyaluronic acid is closely involved in keratinocyte migration and may act positively upon endothelial and fibroblast cells through the adhesion molecule CD44.[9] Thus, HA, with either a lower molecular weight or intermediate molecular weight, can stimulate fibrosis, a process that is very prominent in the pathogenesis of scleroderma. In sclerodermic skin tissue, it is well demonstrated that HA is overproduced and elevated levels of serum hyaluronan in patients with scleroderma were assumed to result from an enhanced synthesis by abnormally activated fibroblasts in the inflammatory process.[14] The presence of elevated serum levels of HA is correlated with various immunological measures, including the presence of anti-topoisomerase I antibody and serum levels of immunoglobulin G and immunoglobulin A. In fact, hyaluronan fragments are endogenous ligands for toll-like receptor 2 and toll-like receptor 4, which are expressed by various immune cells such as macrophages, B cells, and T cells. Some studies[12,15] have shown serum hyaluronan levels are generally higher in proximal scleroderma than in distal scleroderma. Elevated levels of HA occurred predominantly in early-stage patients, while late-stage patients had circulating levels of HA comparable with those observed in control sera.[15]