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Commentary on the Article “Hyaluronic Acid Fillers and ASIA Syndrome: Case Studies”

  • 2 days ago
  • 5 min read


Commentary on the Article

"Hyaluronic Acid Fillers and ASIA Syndrome: Case Studies”


ASIA syndrome (Autoimmune/Inflammatory Syndrome Induced by Adjuvants), first described in 2011 by Professor Yehuda Schoenfeld, encompasses a group of clinical conditions in which the immune response is excessively modulated by substances with an adjuvant role—that is, molecules capable of enhancing the immune response without acting as direct antigens.

These substances directly interfere with innate immunity by inducing an increased response of T lymphocytes and dendritic cells, promoting B-cell memory, and enhancing the neutralizing capacity of antibodies. Adjuvants have the ability to induce pathological clinical pictures and, in some cases, overt autoimmune phenomena characterized by myalgia, myositis or muscle weakness, chronic fatigue, non-restorative sleep, fever, xerostomia, and even neurological manifestations associated with demyelination.

Silicone and vaccines are adjuvants that have been associated with the development of ASIA; however, the true prevalence of the syndrome may be widely underestimated due to the long time interval between exposure to the adjuvant and the onset of symptoms, as well as the non-specific nature of the symptoms.

Establishing a cause–effect relationship (adjuvant–syndrome) would in fact require epidemiological studies with very long-term follow-up (up to 20 years).

ASIA syndrome became relevant in Plastic Surgery when the characteristic symptoms were associated with breast implant placement in augmentation mammoplasty, while in Aesthetic Medicine Koenraad De Boulle raised the issue of a possible association between ASIA and hyaluronic acid–based filler implantation.

It is important to emphasize that hyaluronic acid, being bioidentical by nature, has a very low intrinsic immunogenic potential. However, certain conditions—including biofilm formation and the individual immunological background—may alter the immune response and favor a chronic inflammatory reactivity.

The article presents three cases in which, following a Delayed Inflammatory Reaction (DIR) resistant to conventional treatment, systemic symptoms compatible with ASIA appear.

This allows for several clinical considerations:

All patients showed a predisposition to autoimmune disease: family history of autoimmunity, possible vasculitic history (case 2), previous psoriatic arthritis and chronic nephropathy (case 3). This suggests that the adjuvant does not “cause” the disease, but may anticipate its clinical expression.

It may therefore be hypothesized that ASIA represents the unmasking of a rheumatologic condition that would likely have manifested later in time—highlighting the adjuvant’s role in triggering the clinical expression.

The adjuvant substances involved in the development of ASIA in a given subject may be multiple (for example, breast implants).

In all the cases described, a delayed inflammatory reaction (DIR) to the filler appears first. Removal of the hyaluronic acid improves the signs of local inflammation but is not sufficient in itself to resolve the systemic symptoms typical of ASIA. This suggests that the patient’s individual immunological and genetic predisposition plays a more prominent role than the adjuvant itself, which merely unmasks a subject-specific immune response pattern.

Chronic pharmacological therapy may also play a relevant role, although drugs themselves are not considered adjuvants (in case 3, the patient had a history of immunosuppressive therapies that certainly modulate immune response but do not prevent atypical adverse reactions).

From the aesthetic physician’s perspective, in light of these considerations, whenever a DIR is observed it would be advisable to monitor the patient over the long term in order to promptly recognize any potential development of ASIA and to consider a multidisciplinary approach involving a rheumatologist or clinical immunologist.

Furthermore, before selecting a patient for filler implantation, a thorough medical history should always be obtained, focusing on immune competence, family history of rheumatologic or immunologic diseases, and other risk factors (breast implants, vaccination history, medications impacting the immune system such as immunomodulatory therapies).

In patients at high risk for ASIA, it may be reasonable to perform a hypersensitivity test on the forearm, to be evaluated after 15 days for possible local reactions. Indeed, all clinical manifestations described in the article were characterized by edema (even in the absence of nodules).

Finally, it may be useful to administer a self-assessment questionnaire to investigate the presence of systemic symptoms—even subclinical—such as chronic fatigue, poor sleep quality, arthralgia, and mood disturbances. These are typical symptoms of ASIA and may represent a minor contraindication criterion if the patient has a positive history for immune or rheumatologic disorders (which, in this context, could be considered a major exclusion criterion for filler treatment).


Conclusion

Hyaluronic acid remains a safe and widely biocompatible material.

A recent review analyzing high-level evidence studies confirms the safety and efficacy of hyaluronic acid–based fillers (Kyriazidis I, Spyropoulou GA, Mandrekas A. Adverse Events Associated with Hyaluronic Acid Filler Injection for Non-surgical Facial Aesthetics: A Systematic Review of High Level of Evidence Studies. Aesthetic Plast Surg. 2024 Feb;48(4):745-746).

Fillers do not cause the pathology itself, but may unmask its clinical expression in subjects who would likely have developed it over time. Not all patients with DIR will develop ASIA; however, all reported cases of HA-related ASIA are preceded by a persistent DIR.

The key is not to avoid fillers, but to:


• carefully select patients through an accurate immunological history

• recognize DIR early and monitor patients long term

• when necessary, evaluate patients through a multidisciplinary approach


Authors of the Commentary Contribution:


Patrizia Piersini – Member of the Agorà Executive Committee

Michela Zazzaron – Member of the Agorà Scientific Committee

ABSTRACT OF THE ORIGINAL ARTICLE

SUBJECT OF THE COMMENTARY CONTRIBUTION


Hyaluronic Acid Fillers and ASIA Syndrome: Case Studies

2023 Oct 5;16:2763–2771.


Hyaluronic Acid Fillers and ASIA Syndrome: Case Studies.


Owczarczyk-Saczonek A, De Boulle K.


A continuous increase in the popularity of esthetic procedures with the use of substances as HA has been observed for many years, which might be contributing to an increase in the number of adverse events. The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) can be provoked by hyaluronic acid (HA), which belongs to substances meeting the criteria of adjuvants. Mechanisms of the innate and acquired immune response are activated, leading to the dysregulation of T and B lymphocytes, inability to recognize one’s own antigens, inflammation, damage to one’s own tissues, and ultimately to autoimmunity. The objective of this article is to present a case-series study of patients who developed ASIA syndrome following HA injection after delayed inflammatory reaction (DIR) and emphasize the importance of the need for long-term monitoring after such the reaction. Lack of knowledge about ASIA can lead to delayed diagnosis and serious consequences for the patients. People with a history of immunization reactions, severe allergic reactions, individual predisposition to autoimmunity or family predisposition to autoimmunity and previous exposure to adjuvants require special attention and long-term follow-up. This applies primarily to cases of DIR after the using of bioimplants, especially with treatment resistance, as in our reported cases.


Keywords: hyaluronic acid, bioimplants, ASIA syndrome, immunogenicity


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