As the popularity of hyaluronic acid (HA) dermal fillers increases, so too does the number of complications (Pavicic and Funt, 2013; Urdiales-Gálvez et al, 2018). Although HA dermal fillers are considered to be safe, it is well known that adverse effects do occur (Pavicic and Funt, 2013; De Boulle and Heydenrych, 2015; Urdiales-Gálvez et al, 2018; Philipp- Dormston et al, 2020).
Delayed onset complications are well studied, and can occur weeks to years after treatment. Soft tissue augmentation with dermal fillers is an elective procedure, and not all patients will be suitable for medical reasons.
There are over 80 identified autoimmune disorders. In the UK, four million people are living with an autoimmune condition, and their incidence is increasing (Garcia, 2018). Literature suggests differences of opinion as to whether ‘autoimmune disorders’ should be a contraindication for HA filler placement (Lafaille and Benedetto, 2010; De Boulle and Heydenrych, 2015; Heydenrych et al, 2018; Philipp-Dormston et al, 2020). There is a strong gender bias in the prevalence of autoimmune disorders, which varies according to the actual disorder, but overall estimates suggest around 78% of patients to be female (Fairweather et al, 2008; Ngo et al, 2014). Additionally, in 2018, 90.7% of HA dermal filler procedures were performed on women (International Society of Plastic Surgery (ISAPS), 2019).
A case of a 63-year-old female patient whose medical history included pre-existing autoimmune conditions, psoriasis, psoriatic arthropathy and Sjogren’s syndrome, is reported. Her medication includes etanercept and oral corticosteroids. Historically, she had been treated with various brands of HA dermal filler without complication, over a period of 14 years. There was no evidence of acute autoimmune disease flare- up at the point of treatment with HA dermal fillers. The patient presented 11 months post-treatment with Juvederm® Volift® dermal filler to the right and left marionette lines, complaining of swelling to the left cheek and marionette areas. Examination revealed palpable nodules the left cheek, extending to the body of the mandible marionette and lip areas. At this stage, her right side was unaffected. There was also simultaneous generalised joint swelling, indicative of a flare-up of her autoimmune condition, psoriatic arthropathy. The patient was prescribed two 2-week courses of clarithromycin to no effect, and was consequently referred to a consultant in oral and maxillofacial surgery. Simultaneously, she was treated with oral prednisolone, which successfully settled her systemic autoimmune symptoms, but had no effect on the facial symptoms. A biopsy of the affected tissue was performed, which showed extensive deposits of colourless material with associated granulomatous inflammatory reaction.
Furthermore, left submandibular lymphadenopathy was noted, and a 7-day course of co-amoxiclav was prescribed. An ultrasound examination showed multiple hypoechoic formations in the subcutaneous layer of the left lower lip and cheek areas, which was reported to be likely inflammatory reaction and/or fibrosis. This supported a diagnosis of delayed-onset granulomatous inflammatory reaction following HA dermal filler placement in the marionette region.
The affected areas were treated with hyaluronidase, and there was complete resolution of left-sided symptoms. After 6 days, the patient presented once more, with similar symptoms associated with her right marionette area.
Following discussion with her maxillofacial consultant, a decision was made to treat this area immediately with hyaluronidase, again with complete resolution of symptoms. The patient was advised not to have any further treatment with HA dermal fillers in the future. To date, she has remained asymptomatic, although she is unhappy with the aesthetic result.
Considerations of interest in this particular case were that the delayed onset of facial dermal filler-associated symptoms was apparently coincidental with a flare-up of the patient’s autoimmune condition, psoriatic arthropathy. Of note is that there was a temporal disparity of symptoms to each side of the face. The medication that this patient was taking to treat her psoriatic arthritis is etanercept, which is a tumour necrosis factor inhibitor. It has been used by some clinicians as a last- resort treatment for granulomatous reactions, with some success; others have found the reverse noting development of new silicone granulomas, and, interestingly, induction of sarcoidosis, a granulomatous autoimmune disease, is listed as a recognised side effect (Alijotas-Reig et al, 2013; Alijotas- Reig et al, 2018; National Institute for Health and Care Excellence (NICE), 2020).
Furthermore, the patient’s aesthetic history included treatments with different brands of HA dermal filler. It has been suspected that this could give rise to an increased risk of adverse reactions. This increased risk has not been proven, but it has been shown that when they do occur in these patients, the reactions are more likely to be more severe, and of a chronic nature (Alijotas-Reig et al, 2013).
There was also histological and ultrasonic confirmation of migration of the HA filler product into the patient’s left cheek. Dermal filler migration is a very rare but recognised complication of dermal filler treatment (Kopp et al, 2014; Davy, 2020). However, these aspects of the case are beyond the scope of this piece, and the discussion will focus on the subject of autoimmunity and dermal filler complications.
The ideal dermal filler should cause as little immediate or late adverse tissue reaction as possible (Bentkover, 2009). In its pure state, the HA molecule is present in nearly all species, including bacteria and mammals, and is considered immunologically inert (Ledon et al, 2013; De Boulle and Heydenrych, 2015). HA dermal filler products are linear, unbranched, high molecular weight glycosaminoglycan complex sugars that naturally bind water and provide volume (Bentkover, 2009; DeLorenzi, 2013). They differ in their cross-linkage of the HA, particulate uniformity, size and concentrations (De Boulle and Heydenrych, 2015).
Complications from dermal fillers may be grouped into four categories: allergic, intravascular events, infective and delayed-onset nodules/inflammation (Signorini et al, 2016; Heydenrych et al, 2018).
The term ‘delayed onset nodules’ is widely used to describe a visible or palpable unintended mass that occurs at or close to the injection site of dermal filler (King et al, 2016). They may appear several months to years after treatment (Lowe et al, 2005; Ledon et al, 2013; Pavicic and Funt, 2013; Philipp-Dormston et al, 2020) and are most likely due to inflammatory (immune response to the filler material) or biofilm (infection)-related causes (Ledon et al, 2013; King et al, 2016; Heydenrych et al, 2018; Snozzi and van Loghem, 2018; Urdiales-Gálvez et al, 2018). Clinically, it is difficult to distinguish between the two causes (Pavicic and Funt, 2013).
When HA dermal filler is injected, inflammation occurs (Bentkover, 2009; Alijotas-Reig et al, 2013; Kim et al, 2017). Usually, phagocytosis follows and leads to resorption of biodegradable HA fillers, and it is the rate of this phagocytosis that appears to be the most important factor in determining the longevity of the filler (Bentkover, 2009; Alijotas-Reig et al, 2013; Snozzi and van Loghem, 2018).
True granulomatous inflammation is a systemic, type 4 cell-mediated reaction, and occurs when groups of macrophages are unable to ingest the dermal filler (Bentkover, 2009; DeLorenzi, 2013; Lee and Kim, 2015). It is the most commonly seen delayed hypersensitivity in clinical practice (Chiang et al, 2016; Wang et al, 2020). The failure of effective phagocytosis may lead to encapsulation, potentially giving rise to long-term complications through reactivation of this granulomatous tissue (Alijotas-Reig et al, 2013; Pavicic and Funt, 2013; Bentkover, 2009). In a true type 4 granulomatous process, all sites that were injected with filler material appear adversely affected at the same time (DeLorenzi, 2013; Bhojani-Lynch, 2017).
It is also reported that more concentrated products with a greater degree of cross-linkage increase the risk of granuloma formation because there is increased inflammatory reactivity in the body to the product (Pavicic and Funt, 2013). These products are often chosen because they have a longer duration of effect. Sadeghpour et al (2019) reported a higher incidence of delayed onset nodules in Vycross HA fillers compared to others, which they believed to be immune- mediated, possibly related to the cross-linkage technology and inclusion of pro-inflammatory low molecular weight HA (Sadeghpour et al, 2019). Further to this increased incidence, Creadore et al (2020) recommended avoiding the use of Vycross HA fillers in patients with a history of autoimmune inflammatory disease until more information is gathered regarding the pathogenesis of the delayed onset nodules (Creadore et al, 2020). It has been noted that the patient in this case study was injected with Juvederm® Volift®, which is part of the Juvederm® Vycross range, and gives an estimated product longevity of 18 months (Allergan, 2015).
In this particular case, histological examination confirmed an inflammatory granulomatous reaction with extensive deposits of colourless material. There are variable reported incidence rates for these reactions, ranging from 0.01% to 1.1%, but they are more common in immune-reactive patients, particularly those with active autoimmune diseases (Lowe et al, 2005; Ledon et al, 2013; Pavicic and Funt, 2013; Lee and Kim, 2015; King et al, 2016; Urdiales-Gálvez et al, 2018; Philipp-Dormston et al, 2020).
There is evidence that an acute inflammatory process, delayed for months or years after the injection of filler, might be related to the development of bacterial biofilms or encapsulated colonies of microorganisms that can surround the foreign body (Nairns et al, 2009; Alijotas-Reig et al, 2013; De Boulle and Heydenrych, 2015; Snozzi and van Loghem, 2018; Philipp-Dormston et al, 2020). This can lead to a low-grade, chronic infection, then spontaneous or injury- related reactivation. In this case, the initial prescriptions of antibiotics were given to cover this potential cause. Ultimately, they were of limited effect and did not resolve the symptoms. Additionally, the relationship between immune- mediated hypersensitivity, foreign body granulomatous reactions and infection is intricate (Wang et al, 2020).
Considering the coincidence of symptoms related to the patient’s late-onset granulomatous inflammatory reaction to the HA fillers with the onset of her autoimmune disease symptoms, there is the suggestion that she has encountered a delayed immune-mediated reaction to her HA fillers, related to her autoimmune condition.
Autoimmunity occurs when the body produces autoantibodies, which are antibodies (B lymphocytes) and auto-reactive T cells (T lymphocytes) directed against normal self-components (autoantigens) in genetically predisposed individuals (Ngo et al, 2014). When this causes an illness, it is known as autoimmune disease (Nicholson, 2020). Autoimmune diseases vary considerably in their disease processes, and they may target specific organs or have a systemic effect (Ngo et al, 2014; Nicholson, 2020).
Psoriatic arthritis is a chronic inflammatory autoimmune condition that may or may not follow psoriasis (Lenman and Abraham, 2014). It is estimated that 0.4% of the UK population suffer from the condition, which primarily affects the skin and synovial joints (Choy, 2007). De Boulle and Heyndrych (2015) urge caution in the case of dermal filler use in patients with active psoriatic arthropathy and active psoriasis. T cells are abundant in the inflamed tissues of psoriatic arthropathy, where they play an important role in inflammation and joint damage pathogenesis (Choy, 2007).
In individuals with a predisposing autoimmune genetic background, bioimplants appear to act as T cell activators (Alijotas-Reig et al, 2013; Snozzi and van Loghem, 2018). The HA acts as an adjuvant to the immune response, enhancing it in a non-specific manner, or as a ‘superantigen’, activating the T cells to begin the immune response (Alijotas-Reig and Garcia-Gimenez, 2008; Chaplin, 2010; Alijotas- Reig et al, 2013; 2018; Wang et al, 2020). This highlights the fact that an individual’s immune system reactivity may play a crucial role in a delayed onset inflammatory granulomatous reaction (Alijotas-Reig et al, 2013; Snozzi and van Loghem, 2018).
The genetic profile of autoimmune patients has been investigated by Alijotas-Reig et al (2018). The results are yet to be published, but they report a link between the human leukocyte antigen (HLA) class I and II genes that predispose to autoimmune diseases, and susceptibility to adjuvant triggering of T and B immune activation, leading to inflammatory, immune-mediated, late-onset adverse reactions to biomaterials. They suggest that a predictive risk test may be possible if these results are to be confirmed.
It is this genetic profiling that also makes patients more susceptible to developing autoimmune / autoinflammatory syndrome induced by adjuvants in response to HA (Alijotas-Reig et al, 2018). The name was adopted in 2011 by Schoenfeld and Agmon-Levin to describe clinical and laboratory features of autoimmune or autoinflammatory nature associated with exposure to external stimuli/ adjuvants, including biomaterials such as HA (Shoenfeld and Agmon-Levin, 2011). It remains a phenomenon that is not fully understood, and further research is necessary.
Some publications advise contraindication with certain specific conditions, but advise that the majority of autoimmune conditions appear not to carry an increased risk
Treating autoimmune patients with hyaluronic acid fillers
There is often concern and debate as to whether a patient who gives a history of autoimmune disease should be treated. Confusion is likely, because within the literature, there are conflicting messages. Some publications advise contraindication with certain specific conditions, but advise that the majority of autoimmune conditions appear not to carry an increased risk (De Boulle and Heydenrych, 2015; Heydenrych et al, 2018). However, Lafaille and Benedetto (2010) reported there to be no contraindication to dermal filler treatment in patients with autoimmune conditions, including those specified in the former publications. Others specifically advise to prevent or delay treatment if the autoimmune disease is active (Ponzo et al, 2017; Heydenrych et al, 2018; Philipp-Dormston et al, 2020).
More specific recommendation is given by Creadore et al (2020) to avoid Vycross HA fillers in patients with a history of autoimmune inflammatory disease. Robust published evidence is lacking. Therefore, confusion arises if attempts are made to interpret publications in a more general manner for autoimmune conditions, rather than on a case- by-case basis.
The recommendation to avoid dermal filler treatment during periods of acute autoimmune disease flare-up, when the body is in a stressed or inflamed situation and the immune system is in a hyperactive phase appears sensible (Allergan, 2016; Ponzo et al, 2017). However, this recommendation is of no assistance if HA dermal fillers are placed during periods of apparent autoimmune remission and, subsequently, autoimmune condition flare-ups occur while the filler is in situ.
There is also advice to perform a patch test prior to carrying out treatment on a patient with an autoimmune condition on the Juvederm® Volift® product information leaflet (Allergan, 2016). When discussed within the literature in regard to the general population, without specific reference to autoimmune patients, once again there are differing opinions as to whether it is of value (Micheels, 2001; Grossman, 2005; Lowe et al, 2005; Alijotas- Reig and Garcia-Gimenez, 2008; Alijotas-Reig et al, 2013; Ledon et al, 2013; Chiang et al, 2016; Graivier et al, 2018; Wang et al, 2020). Additionally, there have been reports of hypersensitivity reactions occurring following negative patch testing (Chiang et al, 2016). There is also uncertainty over the effect of immunomodulatory medications and corticosteroids (which are commonly used in the management of autoimmune disorders) on patch testing (Rosmarin et al, 2009). It would be of value to be able to predict patients who are more likely to encounter a delayed onset reaction. However, a request by the practitioner to postpone treatment with HA dermal filler following a skin patch test for the length of time necessary to demonstrate a delayed-onset complication is likely to be considered unreasonable by most patients. Alijotas-Reig and Garcia- Giminez (2008) reported an average latency period of 14 months post-HA dermal filler procedure for onset of delayed, immune-mediated local reaction symptoms.
A structured and balanced process in regard to making the decision to treat or not should be methodically followed. Underlying disease mechanisms must be considered on a case-by-case basis, according to the specific autoimmune disease involved, and understanding of the disease process and its treatment may reveal certain cautions. For example, there is an increased risk of infection in patients on immunosuppressants, such as methotrexate for patients with rheumatoid arthritis or altered healing properties in patients with systemic lupus erythematosus (Demosthenous, 2020). If any medical condition carries an increased risk of dermal filler complication, the clinician must consider the subsequent broader implications for that patient’s health, including specific risks associated with medications and techniques used to treat complications.
The decision to treat patients is always reached following an assessment of the risk-versus-benefit ratio, on a bespoke case-by-case basis. One cannot draw a conclusion as to whether to proceed with HA filler treatment with a mere medical history of autoimmune disease. Practitioners require an understanding of autoimmune disorders, their disease processes, the properties of and the body’s response to dermal fillers so that they may be able to reach a decision on whether to proceed with treatment. Patients with known autoimmune disorders or a history of autoimmune disorders should be counselled as to the risk of a delayed onset complication when considering treatment with HA dermal fillers.
Further research, clarification and consensus reports would be welcomed to assist the practitioner in their decision-making process regarding whether to proceed with HA dermal filler treatment when a patient presents giving a medical history of an autoimmune disorder.
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