Effective Management of Late Inflammatory Nodules Following Hyaluronic Acid Fillers: A Case Series Treated With Methotrexate

Summary:

With the rising popularity of hyaluronic acid (HA) fillers for cosmetic purposes, complications such as delayed-onset edema and nodules have become more frequent. These adverse reactions may be challenging to treat and often require multiple therapeutic strategies. We report 3 cases of women who developed late-onset edema and firm nodules following HA filler procedures. Conventional treatments, including corticosteroids, antibiotics, and hyaluronidase, were insufficient. Oral methotrexate at 15 mg per week was introduced, resulting in complete resolution in all cases within approximately 30 days. Low-dose methotrexate proved to be effective in managing persistent nodules and edema secondary to HA fillers. Methotrexate may represent a promising treatment option for delayed inflammatory responses following HA filler injections. Further prospective studies are needed to validate its safety and efficacy in this context.

Hyaluronic acid (HA) fillers are widely used in minimally invasive aesthetic procedures for facial contouring and rejuvenation. According to the American Society of Plastic Surgeons, more than 3.4 million filler procedures were performed in 2020, despite the COVID-19 pandemic.^1–3

With the increasing number of procedures, late-onset complications have become more common. These include inflammatory nodules and persistent edema that may develop weeks or even months after injection.⁴ Although injection techniques and safety guidelines—such as the 10-point plan—have evolved, management of these adverse events remains complex.⁵

Methotrexate, a folate antagonist with immunosuppressive and anti-inflammatory properties, is widely used in dermatology and rheumatology.⁶ Here, we describe 3 patients with delayed inflammatory responses to HA fillers who responded successfully to low-dose oral methotrexate after failure of conventional therapy.

CASE REPORTS

Case 1

A 67-year-old Brazilian woman received 4 mL of HA filler (Restylane Lyft) in the zygomatic arch, anteromedial malar, and piriform fossa in March 2021. Six days later, she developed significant eyelid edema and swelling in the treated areas. She was prescribed 500 mg cephalexin every 6 hours for 14 days and 20 mg of prednisolone daily for 10 days, tapered gradually for 30 days.

Despite treatment, the patient presented with persistent induration and nodules. Multiple sessions of hyaluronidase (3000 IU total, Biometil) were administered at 7- to 14-day intervals, with only partial regression. After receiving the AstraZeneca COVID-19 vaccine, her symptoms worsened. A new round of hyaluronidase (Permese) and oral corticosteroids was prescribed.

In June 2022, with persistent nodules and elevated blood glucose levels, oral methotrexate at 15 mg per week was initiated alongside prednisolone. Complete resolution was achieved within 3 months and has been maintained to date.

Case 2

Another 67-year-old Brazilian woman underwent HA filler treatments over several sessions between September 2022 and February 2023. Initial treatment involved 2.5 mL of HArmonyCa on the lateral face. Later, she received additional HA fillers: Voluma, Volux, Volift, Volbella, and Volite in the chin, lips, malar region, nasolabial folds, and perioral areas.

In March 2023, after receiving COVID-19 and herpes zoster vaccines and undergoing a period of emotional stress, she developed firm nodules in the previously treated areas (Fig. 1). She was prescribed 40 mg of prednisolone per day for 5 days and clarithromycin, without improvement.

Fig. 1.

Hardened nodules in areas previously treated with HA in the second case.

In May 2023, following negative infection screening, oral methotrexate at 15 mg per week was introduced. The patient experienced full resolution of the nodules within 4 weeks, with no recurrence to date (Fig. 2).

Fig. 2.

Approximately 9 months after treatment with methotrexate in the second case.

Case 3

A 65-year-old Brazilian woman received 3 mL of HA filler (Voluma) in the zygomatic arch, malar region, piriform fossa, and chin, and 1 mL of Volift in the nasolabial folds in October 2019. She remained asymptomatic until April 2020, when she reported localized swelling after spending an extended time in a swimming pool. Symptoms included edema and tenderness in the zygomatic and eyelid areas, along with a firm nodule in the right perioral region (Fig. 3).

Fig. 3.

Edema in the eyelid and zygomatic region after 8 months of treatment in the third case.

The patient had allergic rhinitis (controlled) and was on hormone therapy (estradiol + drospirenone). She received prednisolone for 15 days (40 mg tapered) with partial improvement. Over the next 3 months, symptoms recurred despite multiple antibiotics (moxifloxacin, doxycycline, amoxicillin/clavulanate, ciprofloxacin), antihistamines, and 3 applications of hyaluronidase (1000 IU each, Reductonidase).

In July 2020, oral methotrexate at 15 mg per week was initiated. Within 1 month, the nodules and edema completely resolved, and the patient has remained asymptomatic since (Fig. 4).

Fig. 4.

Three months after starting treatment with methotrexate in the third case.

DISCUSSION

Delayed-onset nodules are considered late complications of HA fillers, typically arising more than 4 weeks after injection.⁷ They are often associated with induration, edema, and erythema, and may persist for several months.

The pathogenesis is multifactorial and may include infectious causes (eg, biofilm) or immune-mediated mechanisms.⁸ Hypersensitivity reactions, particularly delayed type IV reactions mediated by T lymphocytes, are well described. Other factors include impurities in the filler, injection volume, and product composition.⁸

First-line management includes hyaluronidase, corticosteroids, antihistamines, and antibiotics.⁹ However, cases unresponsive to these therapies may require more targeted immunosuppression.

Methotrexate has been used off-label to treat foreign body granulomas and inflammatory nodules caused by various fillers, including silicone and polymethyl methacrylate.^6,10 Its anti-inflammatory effect is mediated by suppression of tumor necrosis factor alpha, interleukin-6, and interleukin-8; reduction in leukocyte recruitment; and inhibition of lymphocyte proliferation.⁶

Although effective, methotrexate must be used cautiously due to potential adverse effects, including hepatotoxicity, bone marrow suppression, and gastrointestinal symptoms. Regular monitoring of liver and renal function and complete blood counts is essential.¹⁰ Pregnancy is an absolute contraindication due to teratogenicity.

CONCLUSIONS

In all 3 cases, patients developed late-onset inflammatory nodules and edema following HA filler injections. Despite multiple attempts with conventional therapies, complete resolution was only achieved after the introduction of oral methotrexate at 15 mg per week. These findings suggest that methotrexate is an effective treatment option for late nodules secondary to HA use. However, prospective long-term studies, with more extensive follow-up and larger samples, are still needed to solidify its efficacy and safety.

DISCLOSURE

The authors have no financial interest to declare in relation to the content of this article.

PATIENT CONSENT

Patients provided written consent for the use of their images.