The Therapeutic Benefit of Allopurinol in the Treatment of Foreign Body Granulomas Caused by Polymethylmethacrylate Microspheres

Abstract

Background:

Polymethylmethacrylate (PMMA) microspheres are permanent dermal fillers used in aesthetic procedures but may cause foreign body granulomas, resulting in chronic inflammation and discomfort. Allopurinol, a xanthine oxidase inhibitor with anti-inflammatory properties, has shown promise in granuloma management, although robust evidence remains limited. This systematic review aims to evaluate the efficacy and safety of allopurinol, alone or in combination with steroids, in treating PMMA-induced granulomas.

Methods:

We systematically searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, and Google Scholar for English-language studies on human participants with PMMA-induced granulomas treated with allopurinol ± steroids. Eligible study designs included randomized controlled trials, cohort and case-control studies, case series, and reports. Two reviewers independently screened articles, extracted data, and assessed bias using Joanna Briggs Institute checklists. Qualitative synthesis was performed because of study heterogeneity and low evidence quality.

Results:

Out of more than 2500 articles identified, 6 studies (5 case reports, 1 case series; n = 8 women, aged 47–83 y) met the inclusion criteria. Granulomas developed 7 months to more than 10 years postinjection. Allopurinol (200–600 mg/d orally, 2–32 mo), alone or combined with steroids, lasers, or antibiotics, improved edema, erythema, tenderness, and nodularity, achieving partial or complete resolution in all cases. Reported adverse events were mild.

Conclusions:

Allopurinol seems to be a safe and potentially effective treatment for PMMA-induced granulomas, offering a steroid-sparing option. However, available evidence is limited to small, low-quality studies. Well-designed randomized controlled trials are needed to confirm efficacy and optimal dosing, and compare therapeutic strategies.

Takeaways

Question: What is the therapeutic efficacy and safety of allopurinol, alone or with steroids, in treating polymethylmethacrylate-induced foreign body granulomas?

Findings: A systematic review of 6 case reports/series (n = 8; age, 47–83 y) showed that allopurinol (200–600 mg/d, 2–32 mo) alone or with steroids, lasers, or antibiotics reduced edema, erythema, tenderness, and nodules, achieving partial to complete resolution. Adverse effects were mild (eg, transient hair loss).

Meaning: Allopurinol is a promising and well-tolerated treatment for polymethylmethacrylate-induced granulomas based on case reports; however, high-quality studies are needed to confirm its efficacy and optimize dosing.

INTRODUCTION

Polymethylmethacrylate (PMMA) microspheres are widely used as permanent dermal fillers because of their durability and biocompatibility.^1,2 However, a notable complication is the formation of foreign body granulomas, a chronic inflammatory reaction to the injected material.³ These granulomas, though relatively rare (≈1% of cases),⁴ can cause pain; swelling; aesthetic dissatisfaction; and, occasionally, functional impairment.^3,4 Unlike hyaluronic acid fillers, PMMA is nonbiodegradable, making its complications more persistent and challenging to treat.⁵ Current management strategies include systemic or intralesional corticosteroids, which may cause adverse effects or fail to fully resolve lesions. Surgical excision is an option, but it is invasive and carries a risk of scarring.^3,6,7 The long-term and often refractory nature of PMMA-related complications highlights the need for safer, more effective, and steroid-sparing therapies.

Allopurinol, a xanthine oxidase (XO) inhibitor primarily used for gout, has emerged as a potential therapeutic agent for managing granulomatous inflammation owing to its anti-inflammatory properties.^8–10 Preliminary studies suggest that allopurinol, alone or combined with steroids, improves symptoms and may reduce the need for prolonged steroid therapy.^8–10 However, evidence remains limited to small case reports and series. In this systematic review, we aimed to synthesize available evidence on the use of allopurinol, with or without steroids, for PMMA-induced granulomas to inform clinical practice and guide future research. It is worth noting that this review relies entirely on case reports and case series without any controlled trials (RCTs), which limits the ability to draw causal inferences or generalize the findings. Therefore, this study serves as an exploratory review to provide a basis for robust studies, rather than evidence of efficacy.

Background

The growing demand for minimally invasive aesthetic procedures has increased the use of soft-tissue fillers. The ideal soft-tissue filler should be safe, biocompatible, resistant to phagocytosis, and able to maintain volume without degradation.¹¹ Hyaluronic acid fillers are the most commonly used and last 6–24 months, but some patients seek more durable results and opt for permanent fillers such as PMMA.⁵ Permanent injectable facial fillers are used to treat wrinkles, restore volume loss, and modify facial structures altered by the aging process.¹² PMMA carries a risk of late complications, including granuloma formation, which can occur from months to more than 10 years postinjection.^4,12 Clinically, granulomas present as nodules, swelling, discoloration, and tenderness, often causing patient distress. Their pathogenesis involves immune activation, infection, or injection technique errors.¹²

Pathophysiology of PMMA-related Granulomas

Granulomas are tumor-like inflammatory lesions formed by aggregates of macrophages, often accompanied by multinucleated giant cells.³ In foreign body granulomas, macrophages are unable to phagocytose the injected PMMA particles, leading to chronic inflammation.³ The process involves sequential steps, including protein adsorption, macrophage adhesion, macrophage fusion, and intercellular crosstalk, culminating in persistent granulomatous inflammation.³

Current Treatment Strategies

No standardized treatment protocol exists for PMMA-related granulomas. Oral and intralesional corticosteroids remain first-line therapy but require prolonged use and are associated with adverse effects. Other options include allopurinol, fumaric acid esters, tetracyclines, nonsteroidal anti-inflammatory drugs, or surgical excision for well-defined lesions.^12–14 Emerging evidence supports the clinical benefits of allopurinol, particularly in steroid-refractory cases.^8–10

Allopurinol and Its Anti-inflammatory Properties

Allopurinol is an XO inhibitor approved for the prevention of gout and chemotherapy-induced hyperuricemia.^15–18 By blocking the conversion of hypoxanthine to xanthine and uric acid, it reduces uric acid levels and oxidative stress.¹⁷ Beyond its urate-lowering effect, allopurinol reduces reactive oxygen species production, suppresses proinflammatory cytokines, and modulates immune cell activity. These mechanisms support its use as an adjunct therapy in inflammatory conditions, including PMMA-induced granulomas.^19–23

XO inhibition modulates granulomatous inflammation by preventing the secretion of proinflammatory cytokines.^24,25 XO catalyzes the production of uric acid and superoxide radicals from purine bases.^24,25 Uric acid can initiate a series of inflammatory responses by activating the inflammasome and NF-κB pathways in endothelial cells, inducing the release of proinflammatory cytokines. Simultaneously, XO generates hydroxyl radicals from superoxide intermediates, amplifying oxidative stress and inflammation.^24,25 In granulomatous conditions, allopurinol inhibits granuloma formation by suppressing multinucleated giant cell development via the inhibition of the monocyte P2X7 receptor and intracellular adhesion molecule-1, which contribute to granuloma formation.²⁶

Other steroid-sparing agents (minocycline and doxycycline), in addition to their antibiotic properties, have been shown to exhibit anti-inflammatory and antiapoptotic activities by inhibiting nitric oxide synthases, cyclooxygenase-2 and phospholipases A2, and matrix metallopeptidases.²⁶ Clinical studies have reported minocycline’s efficacy in inflammatory acne, noninfectious dermatitis, rosacea, bullous dermatoses, and neutrophilic dermatoses; however, doxycycline has been preferred recently because of its similar efficacy with fewer complications.²⁶

Aim and Objectives

Aim

The aim of this study is to evaluate the therapeutic efficacy and safety of allopurinol, alone or with corticosteroids, in the treatment of PMMA-related foreign body granulomas.

Objectives

• Assess the effectiveness of allopurinol in reducing inflammation and resolving granulomas.

• Evaluate potential synergistic effects with corticoste-roids.

• Determine the safety profile and report adverse effects of allopurinol in this context.

• Summarize available data on dosing, administration route, and treatment duration.

• Provide considerations for clinical management of PMMA-induced granulomas based on the available evidence.

METHODS

Study Design

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PROSPERO registration number is CRD420251142672.

Eligibility Criteria

Inclusion criteria were studies published in English between January 2000 and July 2025, focusing on individuals with PMMA-induced foreign body granulomas treated with allopurinol, with or without steroids, and reporting clinical outcomes such as granuloma resolution, reduction in inflammation, recurrence rates, or adverse events. Exclusion criteria included animal studies, in vitro studies, investigations not specifically addressing PMMA-induced granulomas, nonhuman studies, studies lacking clinical outcomes, non-English publications, and studies with insufficient data for extraction. Eligible study designs included RCTs, cohort studies, case-control studies, case series, and case reports, all published in peer-reviewed journals.

Information Sources

A comprehensive literature search was performed in PubMed, Embase, Scopus, Web of Science, Cochrane Library, and Google Scholar. Reference lists of included articles were also manually screened for additional publications.

Search Strategy

The search strategy combined keywords and Medical Subject Headings, including allopurinol, PMMA, foreign body granuloma, dermal fillers, steroids, corticosteroids, inflammation, complications, and adverse effects. Boolean operators (AND, OR) were used to refine the searches.

Selection Process

Two independent reviewers screened titles and abstracts for eligibility based on the predefined inclusion and exclusion criteria. Full-text articles of potentially relevant studies were retrieved and assessed for inclusion. Any discrepancies between reviewers were resolved through discussion.

Data Collection Process

Data were extracted by 2 independent reviewers using a standardized template. Extracted information was cross-verified for accuracy, and disagreements were resolved through consensus.

Data Items

Extracted data included study characteristics (author, year of publication, study design, sample size), patient demographics (age, sex, relevant medical history), treatment details (allopurinol dosage, type and dosage of corticosteroid, route of administration, duration of therapy), and reported outcomes (granuloma resolution rates, reduction in inflammation, recurrence rates, adverse events).

Study Risk of Bias Assessment

All eligible studies were case reports or case series; the Joanna Briggs Institute critical appraisal checklists for case reports and case series were applied to evaluate methodological quality, focusing on aspects such as clear reporting of patient history, clinical condition, treatment details, and outcomes.

Synthesis Methods

A qualitative synthesis was conducted using a narrative summary to describe study characteristics, treatment protocols, and outcomes, identifying patterns in the efficacy and safety of allopurinol for PMMA-induced granulomas. Quantitative synthesis via meta-analysis using random-effects models was planned if sufficient homogeneity existed across studies, and statistical heterogeneity was evaluated using the I² statistic. However, owing to the eligibility of only case reports and series, only a qualitative synthesis was conducted.

Certainty Assessment

Given the type of studies included, the certainty of evidence was not formally graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. Included studies were either case reports or series with low evidence levels.

RESULTS

More than 2500 articles were identified in the initial search, but only 6 met the inclusion criteria (Fig. 1). The search yielded no RCTs, prospective or retrospective cohort studies, or case-control studies, underscoring the emerging nature of allopurinol and its reliance on case reports and case series.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for the included studies.

Characteristics of the Included Studies

The 6 included studies, published between 2003 and 2020, comprised 5 single case reports and 1 case series. (See table, Supplemental Digital Content 1, which displays characteristics of the included studies, https://links.lww.com/PRSGO/E794.) All reports involved women aged 47–83 years who developed delayed granulomatous reactions following Artecoll (PMMA/collagen) filler injections. The period between filler injection and clinical presentation of granulomas varied widely (from 7 mo to >10 y). Clinical manifestations of foreign body granulomas typically include swelling, erythema, and nodules. Artecoll was the PMMA filler used in most cases.

Effectiveness of Allopurinol in PMMA-related Inflammation and Granuloma

Across the included reports, allopurinol demonstrated consistent effectiveness in reducing inflammation and granuloma size, with improvements in symptoms, such as edema, erythema, tenderness, and nodule firmness. In cases where allopurinol was used alone,^8,9 outcomes were positive, with gradual resolution during 4–24 weeks. Fischer et al²⁷ reported gradual swelling reduction after 6 weeks on allopurinol (up to 600 mg/d), with partial nodule resolution and ulcer healing during an additional 16 weeks in a 48-year-old woman with disfiguring facial edema. Similarly, Reisberger et al.⁹ reported reduced tenderness and erythema in a 61-year-old woman after 8 weeks of treatment (starting at 200 mg/d and increasing to 600 mg/d), which progressed to softening and color improvement during the next 8 weeks, with only slight discoloration remaining at 24 weeks. In a separate case report, Silveira et al⁸ observed significant lesion healing within the first month of allopurinol treatment in a 56-year-old woman (initially 200 mg/d, then 300 mg/d), restoring the skin to a physiological state with no relapse at the 3-month follow-up. Redondo et al²⁸ found that a daily dose of 300 mg for 2 months was effective in achieving complete resolution of the lesions within 2 months, with no recurrence noted at the 1-year follow-up.

In combination therapies,^29,30 allopurinol contributed to the resolution of foreign body granulomas. Gelfer et al²⁹ described 3 cases where allopurinol was combined with intralesional triamcinolone and other modalities. In case 1, the patient achieved remission 6 months after the postfinal treatment, case 2 showed partial resolution after 2.5 years, and case 3 had complete resolution after 13 months. González-Delgado et al³⁰ reported a slow but steady improvement in an 83-year-old woman treated with allopurinol (300 mg/d) plus cyclic mometasone furoate, achieving full lesion control after 8 months, including resolution of edema and scarring. Based on the included cases, allopurinol effectively reduced inflammation and granuloma formation. It should be noted that this review is based solely on case reports and case series, lacking controlled trials; thus, it serves as an exploratory overview to inform future robust studies rather than providing evidence of efficacy.

Safety Profile and Potential Adverse Effects of Allopurinol

All reports indicated that allopurinol treatment was well tolerated by the patients. Overall, the safety profile of allopurinol was favorable across studies, with minimal adverse effects reported. Most studies reported no adverse effects.^8,9,30 Minor events included transient hair loss and mild, clinically insignificant liver enzyme elevations, which did not necessitate treatment discontinuation.³⁰ No serious adverse events were reported.

Optimal Dosing, Administration Routes, and Treatment Duration

Allopurinol was exclusively administered orally, with an initial dose of 200–300 mg/d and a maximum dose of 600 mg/d in 2 reports. (See table, Supplemental Digital Content 2, which displays optimal dosing, administration routes, and treatment duration based on the included cases, https://links.lww.com/PRSGO/E795.) The duration of prescription was 4 months for monotherapy and 8–32 months when combined with other treatments. No studies reported intravenous or topical administration. Evidence suggests starting at 200 mg/d with gradual titration if needed, and maintaining treatment for several months to ensure sustained remission. Figure 2 shows the proposed staged management of PMMA-induced granulomas.

Fig. 2.

Staged management of PMMA-induced granuloma.

DISCUSSION

Principal Findings

This systematic review evaluated the therapeutic benefits of allopurinol, with or without steroids, in managing PMMA-induced foreign body granulomas. Across all included reports, allopurinol was associated with consistent clinical improvements, including reductions in edema, erythema, tenderness, and nodule firmness, leading to gradual lesion resolution over weeks to months.^8,9,27,31 These results align with the established anti-inflammatory mechanisms of allopurinol, including the inhibition of reactive oxygen species and proinflammatory cytokines,^19–23 which may attenuate the macrophage-driven granulomatous response.³

Similar outcomes have been reported in silicone-associated granulomas,²⁸ suggesting a broader therapeutic potential for allopurinol in foreign body–related inflammation. Clinically, this positions allopurinol as a viable alternative or adjunct to corticosteroids, potentially reducing the risks associated with prolonged steroid use, such as adrenal suppression, skin atrophy, and systemic metabolic effects.⁷ In aesthetic medicine, where PMMA complications can persist for years,^5,12 allopurinol may improve both patient comfort and cosmetic outcomes.^3,4

However, treatment duration varied widely (4–32 mo), highlighting the need for individualized therapy based on disease severity and clinical response. More robust studies are required to define optimal dosing, timing, and treatment duration.

Dosing, Monitoring, and Safety Considerations

Across the reviewed cases, oral doses ranged from 200 to 600 mg/d, usually starting low and titrated upward as needed. Monotherapy typically required 4–6 months, whereas combination regimens often required longer courses. Nonetheless, the lack of uniform dosing strategies underscores the need for standardized treatment protocols.

The safety profile of allopurinol was favorable, with only mild, reversible adverse effects such as transient hair loss, slight discoloration, and mild liver enzyme elevation.^9,27 No discontinuations due to adverse events were reported. This compares favorably with corticosteroids, whose long-term use is limited by systemic toxicities.^31,32 Accordingly, allopurinol may be particularly valuable when corticosteroids are contraindicated or poorly tolerated.

Several other considerations before using allopurinol are mostly related to potential drug interactions, implications in specific populations, regular monitoring, and treatment duration. The human leukocyte antigen B (HLA-B) plays a crucial role in the immune system; its variant, HLA-B*58:01 allele, is most common in the Asian population and is strongly associated with severe cutaneous adverse reactions during treatment with allopurinol.^33,34 Compared with African and White populations, Asian ethnicities may have a higher risk of serious skin cutaneous reactions if they have the B*58:01 allele.³⁵ Consequently, clinicians recommended testing for HLA–B*58:01 before starting allopurinol in the Asian population.^33,34 Potential drug interactions should also be considered when using allopurinol. Evidence indicates that the interaction of allopurinol with azathioprine or 6-mercaptopurine can lead to serious adverse outcomes, such as severe agranulocytosis and pancytopenia.^35–37 Baseline and regular monitoring (2–5 wk) of complete blood count, liver function tests, renal function, and serum uric acid levels is required following allopurinol administration.³⁷ Limited and low-quality evidence suggests optimal treatment responses after 4 months of allopurinol treatment, with no relapse cases in the included studies. Conditions requiring allopurinol discontinuation include the development of allopurinol hypersensitivity syndrome, skin rashes, and other side effects such as Stevens-Johnson syndrome and toxic epidermal necrolysis.³⁷

Consider allopurinol if the patient:

• Has confirmed PMMA-induced foreign body granuloma (eg, following Artecoll or similar PMMA/collagen filler injections), with a delayed onset (7 mo to >10 y postinjection);

• Has experienced recurrence or failure to resolve inflammation or nodule firmness despite adequate treatment with corticosteroids;

• Has evidence of ongoing inflammation attributed to macrophage response or reactive oxygen species, where allopurinol’s anti-inflammatory mechanisms (XO inhibition and reduced proinflammatory cytokines) may attenuate granuloma progression;

• Has experienced failure in prior treatments, such as steroids alone, shown partial response, or is contraindicated;

• Has no high risk for HLA-B58:01-associated severe cutaneous adverse reactions, or has negative HLA-B58:01 testing;

• Has no concurrent use of azathioprine or 6-mercapto-purine;

• Has feasible baseline and ongoing laboratory monitoring for CBC, LFTs, renal function, and serum uric acid at baseline, and then every 2–5 weeks; and

• Has no history of allopurinol hypersensitivity syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, or severe rash with prior exposure.

Limitations

The evidence base for allopurinol in treating PMMA-induced foreign body granulomas remains limited to case reports and small series, with no RCTs or comparative studies. This inherently limits generalizability and precludes firm conclusions regarding efficacy. The heterogeneity in dosing regimens, treatment duration, and concurrent therapies further complicates interpretation.^8,27–30 Additionally, small sample sizes and short follow-up periods (as little as 3 mo in some cases) may underestimate recurrence risk or late adverse effects.⁸ Additionally, restricting the search to English-language studies may have excluded relevant non-English publications, particularly from regions with high PMMA filler use. There is a potential publication bias due to the reporting of positive outcomes in case reports and series, as they often highlight successful treatments over unsuccessful ones.

Future Directions

Well-designed RCTs, cohort studies, and mechanistic investigations are needed to establish the efficacy, optimal dosing, and duration of allopurinol therapy for foreign body granulomas. Future comparative trials against corticosteroids and other immunomodulators would also clarify allopurinol’s place in therapy. Standardized treatment protocols, long-term follow-up, and recurrence monitoring are critical for developing evidence-based clinical guidelines.

CONCLUSIONS

Emerging evidence from case reports and series suggests the potential safety and effectiveness of allopurinol for PMMA-induced foreign body granulomas, either alone or in combination with corticosteroids. Its favorable safety profile and steroid-sparing potential make it an attractive therapeutic choice. However, current data are limited to low-level evidence, and high-quality studies are urgently needed to confirm its efficacy and safety and to define standardized treatment regimens.

DISCLOSURE

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