Hyaluronic Acid-based Products are Strictly Contraindicated in Scleroderma-related Skin Ulcers

Introduction. Evidence of the role of hyaluronic acid (HA) in the tissue repair process is extensive. Hyaluronic acid produces a positive effect on skin ulcer healing, so many companies produce it in various topical applications. Objective. This retrospective, observational study examined the use of different HA-based products in patients with chronic skin ulcers of various etiologies (vascular, scleroderma, postoperative) to assess the indication, effectiveness, and possible adverse reactions. Materials and Methods. A retrospective case review was conducted on 79 patients presenting to the Department of Dermatology of the Spedali Civili (Brescia, Italy) with multiple chronic skin ulcers of the legs of various etiologies. The authors counted a total of 106 chronic wounds with granulating appearance but not responsive to common wound dressings; for this reason, these wounds were treated with a HA-based product. The efficacy of the treatment was evaluated by dividing the population into 2 groups: sclerodermic (41 ulcers) and nonsclerodermic (65 ulcers). Results. Initial results confirmed HA-based products were effective for healing chronic skin wounds. However, when wounds are grouped by etiology, it was evident that patients with sclerodermic ulcers showed a rapid inflammatory response that led to a clinical deterioration and worsening of skin ulcers (92.7%). In contrast, patients with noninflammatory ulcers (vascular, postoperative) had the severe inflammatory event reduced to 1.5%, with a recovery of 98.5%. Conclusions. The negative effects of HA-based products on a patient with scleroderma could be explained by the fact that HA can produce a proinflammatory effect causing keratinocyte migration.

Evidence of the role of hyaluronic acid (HA) in the tissue repair process is extensive. It is well known that HA is produced by various cell types at different stages of their life cycle and that it performs many functions within the wound healing process due to its polysaccharide structure in the extracellular matrix (ECM).¹ As a glycosaminoglycan of the ECM that is normally produced by mesenchymal cells, HA is strongly elevated during embryogenesis and tissue injury inflammation and repair as well as in tumor invasion and metastasis. Hyaluronic acid is closely involved in keratinocyte migration and may act positively upon endothelial and fibroblast cells through the adhesion molecule CD44.^1,2 Due to hygroscopic, rheological, and viscoelastic properties, HA influences the surrounding extracellular environment through complex molecular interactions with both cellular and matrix surface receptors. 

Hyaluronic acid exists in 3 forms based on molecular weight that act in different directions on tissue.³ Higher molecular weight HA (1000 kDa) has an anti-angiogenic effect.⁴ Intermediate-sized HA oligomers (200 kDa) are involved in tissue repair through an inflammatory effect; in fact, they stimulate the expression of inflammatory chemokines, macrophages, eosinophils, endothelial cells, and epithelial cells.³ Finally, lower molecular weight HA fragments (20 kDA) stimulate dendritic cells and upregulate both collagen I and III gene expression in fibroblastic cells.³ Due to its biocompatibility, HA has found wide use in the medical and cosmetic fields, including the healing of chronic skin wounds. It appears that HA produces a positive effect in the healing of chronic skin ulcers of various etiologies such as venous leg ulcers, burns, and postsurgical wounds.^5,6 Many companies produce HA in various topical applications, including pads, creams, and substrates, as HA has been shown to improve healing time. Hyaluronic acid also has been shown to exhibit an important analgesic effect on pain that influences patient quality of life.⁷

Indeed, chronic wounds significantly decrease quality of life in a number of ways, such as reduced mobility, pain, unpleasant odor, sleep disturbances, social isolation and frustration, and inability to perform everyday duties.⁸ Psychological factors may not only be a consequence of delayed healing but also may be influenced by choosing the right treatment between the variety of products on the market. 

The authors conducted a retrospective observational study on the use of HA-based products, prescribed in the year 2011, for patients with chronic ulcers of various etiologies (vascular, scleroderma, and postoperative) consecutively presenting to the Department of Dermatology of the Spedali Civili (Brescia, Italy) in order to assess indication, effectiveness, and possible adverse reactions.

A retrospective case review was conducted on 106 chronic wounds of various etiologies (vascular, scleroderma, and postoperative) with granulating appearance unresponsive to common topical wound dressings (alginates-carboxymethylcellulose, hydrogel, polyurethane foam, collagen). A total of 79 patients (55 women, 24 men) were enrolled with a mean age of 71 years (range, 40–98 years). The 79 patients and relative 106 skin ulcers were divided in 2 groups: nonsclerodermic and sclerodermic (Table 1). Ulcers of neoplastic origin, iatrogenic ulcers, diabetic ulcers, and ulcers of recent onset (< 6 weeks) were excluded from the data source. In addition, ulcers for which HA is not indicated (infected ulcers and ulcers covered with necrotic tissue) were excluded from the study. The HA-based products used included Ialuset cream (300 kDa; IBSA Farmaceutici Italia, Lodi, Italy), Hyalofill-F (400 kDa; Fidia Farmaceutici s.p.a., Abano Terme, Padua, Italy), and Bionect Start (160 kDA; Fidia Farmaceutici s.p.a.). The products were applied according to the manufacturer’s package insert.

Of the 106 treated wounds, 56 (52.8%) ulcers achieved healing with no side effects, 40 (37.7%) ulcers developed clinical worsening (intense periwound skin erythema, pain, and increasing ulcer dimension) and discontinued therapy, and the remaining 10 (9.4%) lesions developed transient periwound skin erythema and burning but did achieve healing. For the 40 worsening ulcers, a microbiological examination of the wound bed was performed due to suspicion of a superinfection; all sample cultures were negative for bacterial growth. A patch test also was performed on these patients with the HA-based products “as-is,” showing to be negative for allergic contact sensitization.

If the percentage of ulcers that achieved healing were analyzed, 3 different results emerged: patients who healed without inflammation, patients who healed with a transient erythema, and a third skin reaction in which the patients worsened until the discontinuation of HA-based product use.

Furthermore, if the data are stratified based on ulcer etiology, inflammatory ulcers versus noninflammatory ulcers, 2 groups are identified (Table 2, Figure). Group 1 is represented by patients with noninflammatory ulcers (vascular and postoperative) while group 2 is represented by only patients with scleroderma-related ulcers. In group 1, 65 patients (42 women, 23 men) with 65 ulcers were treated. The average age of the patient was 74 years (range, 40–98 years). In group 2 overall, 41 granulating skin ulcers in 14 patients with scleroderma (13 women, 1 man; lesion:patient ratio, 2.9) with a mean age of 65 years (range, 43–84 years). All 14 patients were affected with diffuse cutaneous systemic sclerosis and under continuous treatment with bosentan and periodically pulsed intravenous prostanoid.

Of the 65 ulcers treated in group 1, 54 (83.1%) achieved healing, 10 (15.4%) developed transient and nonspecific inflammatory reactions (erythema, edema, burning, redness) but ultimately healed, and 1 (1.5%) showed clinical deterioration with an increase in size and pain, in which case the treatment was interrupted.

Of the 41 ulcers treated in group 2, 38 (92.7%) developed an immediate increase in periwound skin inflammation, increased pain and burning sensations, and increased ulcer size, forcing the patient to stop treatment and anticipate medical consultation. In these patients with multiple ulcers, all wounds showed the same clinical behaviors. After the discontinuation of local therapy with HA, a steroid topical application was needed to reduce inflammation. The remaining 3 ulcers of the 41 treated (7.3%) belonged to the same patient who had an inflammatory reaction, but the ulcers finally healed.

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 known¹¹; 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

A limitation of this study is its retrospective nature. The authors evaluated only 3 types of HA-based products that are present inside the authors’ hospital. A larger study comparing all products containing HA on the international market would help highlight the most effective HA-based products. Although the data herein clearly underline that different etiologies of skin ulcers may modify the clinical response to local therapy, a wider study with more patients will certainly be useful in strengthening this hypothesis.

Even though within the authors’ dermatology practice sclerodermic ulcers represent about 2% of total patients followed for skin ulcers, the particular pathogenesis of the disease and several comorbidities associated implicated a large expenditure of energy in terms of time consulting with the patient, selecting the appropriate wound treatment, and coordinating systemic therapy (prostanoid, endothelin receptor antagonist, immunosuppressant agent). As evident by the data herein, if used on vascular deficiency ulcers (ie, venous, arterial, or mixed ulcers), HA is useful in aiding the wound healing process. However, broad-scale application without adequate medical screening of patients who are candidates for treatments with HA leads to an erroneous assessment of the effectiveness of the product. In this sense, the physician’s role in the management of a cutaneous ulcer is to recognize the pathogenic mechanism leading to the formation and chronic nature of the same by selecting the most suitable local therapy in each individual case. Thus, despite that sclerodermic ulcers are limited in number, especially for the pathogenesis that underlies the disease, it is recommended not to use topical HA-based products for patients with scleroderma. It also is still unclear whether other types of ulcers of inflammatory etiology (autoimmune, pyoderma gangrenosum, vasculitis) can present the same contraindication. In this sense, additional case studies would be helpful. 

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

Affiliation: Department of Dermatology, Spedali Civili, University of Brescia, Brescia, Italy 

Correspondence: Daniele Cammalleri, MD, University of Brescia - Spedali Civili, Dermatology, Piazzale Spedali Civili 1, Brescia, Italy 25123; danielecammalleri@gmail.com 

Disclosure: The authors disclose no financial or other conflicts of interest.