Dermal fillers do not induce upregulation of NLRP3 inflammasomes or expression of inflammatory cytokines in granulomas.

BACKGROUND: Filling materials have increasingly been used in aesthetics over the last decades. Understanding the pathophysiology of granuloma formation as a very relevant unwanted side effect of filler application may be essential to help avoid these adverse events. AIMS: Our aim was to investigate the role of the inflammasome in the formation of filler granuloma, as a central column of the innate immune response. METHODS: RPMI 1640 medium was used for growth of THP-1 cells and the induction of THP-1 macrophages. Sonication was applied in order to crush the acrylic particles of the filler. ELISA was the method of analysis for the specific cytokines. Biopsy specimens of filler granuloma were analyzed by various immunohistochemical methods. GraphPad Prism 5 software was used for the statistical data analysis. RESULTS: Neither was the sensor NALP3 overexpressed, nor could an elevated expression of cleaved IL-1ß, IL-18, or IFN-γ be detected. Furthermore, no increased expression of IL-8 or IL-1ß was detectable in vitro. CONCLUSION: No increased inflammasome activation could be observed; however, filler granulomas were infiltrated with granulocytes and macrophages. Therefore, we speculate that an unspecific immune response might be the key player in the formation of filler granuloma.

Current status of surgery in dermatology.

An article titled "Current issues in dermatologic office-based surgery" was published in the JAAD in October 1999 (volume 41, issue 4, pp. 624-634). The article was developed by the Joint American Academy of Dermatology/American Society for Dermatologic Surgery Liaison Committee. A number of subjects were addressed in the article including surgical training program requirements for dermatology residents and selected advances in dermatologic surgery that had been pioneered by dermatologists. The article concluded with sections on credentialing, privileging, and accreditation of office-based surgical facilities. Much has changed since 1999, including more stringent requirements for surgical training during dermatology residency, and the establishment of 57 accredited Procedural Dermatology Fellowship Training Programs. All of these changes have been overseen and approved by the Residency Review Committee for Dermatology and the Accreditation Committee for Graduate Medical Education. The fertile academic environment of academic training programs with interaction between established dermatologic surgeons and fellows, as well as the inquisitive nature of many of our colleagues, has led to the numerous major advances in dermatologic surgery, which are described herein.

Antibody-induced failure of botulinum toxin a therapy in cosmetic indications.

BACKGROUND: Botulinum toxin (BT) is a safe and effective treatment for cosmetic indications. Formation of BT antibodies can occur but has previously been reported in cosmetic indications in two cases only. OBJECTIVE: To report another four patients with this phenomenon. OBSERVATIONS: Two patients received abobotulinumtoxinA; one received the current formulation of onabotulinumtoxinA and one both abobotulinumtoxinA and onabotulinumtoxinA. Complete secondary therapy failure (CSTF) occurred after 3-, 5-, 10-, and 13-injection series; cumulative treatment times of 18, 16, 25, and 65 months; and cumulative doses of 240 MU onabotulinumtoxinA, 245 MU abobotulinumtoxinA, 1,180 MU abobotulinumtoxinA, and 120 MU onabotulinumtoxinA/270 MU abobotulinumtoxinA, respectively. Average interinjection intervals were 87, 273, 150, and 119 days, and average single doses were 80 MU onabotulinumtoxinA, 68 MU abobotulinumtoxinA, 82 MU abobotulinumtoxinA, and 30 MU abobotulinumtoxinA/30 MU onabotulinumtoxinA. Risk factors for CSTF included booster injections (2 patients) and increased immune system reagibility (1 patient). BT antibody titers were 2.7, 7.0, and more than 10.0 mU/mL on the mouse diaphragm assay. CONCLUSIONS: CSTF can occur after cosmetic BT injections in patients with high immune system reagibility and in patients receiving booster injections, but also in unremarkable patients with typical treatment parameters. Its incidence is unknown. Recommended treatment parameters may reduce the risk of CSTF, but may not eliminate it.

The current state of treatment of adverse reactions to injectable fillers.

BACKGROUND: Adverse reactions to injectable filler may be challenging to treat. The spectrum of treatment options ranges from immunomodulatory drugs (e.g., glucocorticosteroids) to antibiotics to laser therapy and surgery. OBJECTIVES: To assess how adverse reactions were treated and how they processed over time. MATERIALS AND METHODS: Participants from the Injectable Filler Safety (IFS) Study were reinterviewed to obtain data on the course of adverse reactions and the therapy. RESULTS: Forty-one participants from the IFS Study were reinterviewed; 35 (85%) received treatment, 17 (41%) with a combination of drug therapy and surgery, 14 (34%) with drug therapy only, and four (10%) with a surgical intervention. Six (15%) did not receive any treatment. Fifty-one percent of all of the treated participants reported treatment-related adverse reactions. Participants with more severe adverse reactions were more likely to be treated with a combination of drugs and surgery. In all participants, adverse reactions improved. CONCLUSION: We certainly need more evidence. Reporting positive and negative treatment outcomes is important to improve our knowledge regarding these reactions. Therefore, registries focusing on adverse reactions to injectable fillers and their treatment should be encouraged. The authors have indicated no significant interest with commercial supporters.

The spectrum of adverse reactions after treatment with injectable fillers in the glabellar region: results from the Injectable Filler Safety Study.

BACKGROUND: For the glabellar region, severe partly vascular adverse events have been reported after treatment with injectable fillers. METHODS AND MATERIALS: For this study, data from the Injectable Filler Safety Study, a German-based registry for those reactions, was analyzed to characterize adverse events seen in the glabellar region. Patients were analyzed descriptively. RESULTS: Forty of 139 registered patients reported adverse events in the glabellar region. All patients were female, with an average age of 52.3. Nineteen patients with adverse reactions to hydroxyethylmethacrylate (HEMA) and ethylmethacrylate (EMA) in a fixed combination with hyaluronic acid (HA) and 10 patients with adverse reactions to different hyaluronic acid products were reported; five patients reacted to poly-L-lactic acid (PLA). The most common adverse reactions to HEMA/EMA in HA and PLA were nodules and hardening. In HA-treated patients, erythema and inflammation, swelling, and pain were most frequent. The adverse reactions to HEMA/EMA in HA were severe in 50% of the patients. Severe adverse reactions were found to a lesser extent in patients treated with HA and PLA. Potential vascular complications were documented in only two patients. CONCLUSION: Adverse reactions seen in the glabella are overwhelmingly product associated and to a lesser extent location associated. Vascular complications with necrosis and ulceration were rare.

Electron microscopic documentation of late changes in permanent fillers and clinical management of granulomas in affected patients.

BACKGROUND: The manufacturers of permanent injectable fillers claim that their products are widely inert, biocompatible, atoxic, and nonimmunogenic. There are polymer gels without microparticles on the market and combination products that use collagen suspension or a hyaluronic acid gel as a vector to which polymer microspheres or polygonal particles are added. The filling effect of the polymer gels is based on the volume injected and, for the combination gels, partly on the volume injected and partly on the intended host foreign-body reaction to the microparticles. Foreign body reactions that are seen as inflammatory, sometimes disfiguring, nodules may develop years later at the injection sites. OBJECTIVES: Permanent fillers differ with respect to composition and chemical and biological characteristics. There have been reports that intend to explain how host tissue reacts with different permanent fillers and how adverse reactions differ depending on the filler used. The changes that some of the permanent fillers undergo during years of residence in human tissue have not been included in this discussion. These structural changes may be one of the reasons why adverse reactions to permanent fillers occur clinically with a delay of several years. METHODS: In a series of 10 patients who had been injected with a permanent filler of hydroxymethylmethacrylate and ethylmethacrylate (40%) in hyaluronic acid gel (60%) and had developed adverse reactions with inflammatory nodules after variable time elapsed, biopsies could be obtained for histologic and electron microscopic examinations. RESULTS: After 2 years in all specimens, changes of degradation of the filler material could be detected. Bacteria were not found in any of the specimen. In 40% of the particles, the size of the particles did not correspond to the size declared by the manufacturer (45-65 microm) and was smaller, thus being more susceptible to phagocytosis. CONCLUSIONS: Inflammatory nodules due to adverse reactions to permanent fillers containing microparticles with a hydrophobic surface were treated with good results with a regimen of allopurinol and intralesional injections with a mixture of fluorouracil and low-dose triamcinolon.

An overview of the cosmetic treatment of facial muscles with a new botulinum toxin.

Botulinum toxin (BTX) is used nowadays in a much more differentiated way with a much more individualized approach to the cosmetic treatment of patients. To the well known areas of the upper face new indications in the mid and lower face have been added. Microinjection techniques are increasingly used besides the classic intramuscular injection technique. BTX injections of the mid and lower face require small and smallest dosages. The perioral muscles act in concert to achieve the extraordinarily complex movements that control facial expressions, eating, and speech. As the mouth has horizontal as well as vertical movements, paralysis of these perioral muscles has a greater effect on facial function and appearance than does paralysis of muscles of the upper face, which move primarily in vertical direction. It is essential that BTX injections should achieve the desired cosmetic result with the minimum dose without any functional discomfort. In this paper the three-year clinical experience with average dosages for an optimal outcome in the treatment of facial muscles with a newly developed botulinum toxin type A (Xeomin) free from complexing proteins is presented.

Decrease of reported adverse events to injectable polylactic acid after recommending an increased dilution: 8-year results from the Injectable Filler Safety study.

BACKGROUND: Injectable fillers are widely used in aesthetic medicine. Polylactic acid (PLA) is a semipermanent filler that needs to be diluted with sterile water before injection. PLA has been associated with an increased risk of adverse reactions, specifically nodule formation. OBJECTIVE: To describe adverse reactions to PLA and potential risk factors based on a partly population-based registry over an 8-year period. METHODS: The Berlin registry is a partially population-based registry where dermatologists, plastic surgeons, and other specialists are contacted regularly and asked to report patients with adverse events to injectable fillers substances. Additional patients were derived from private practices outside of Berlin. The patients were assessed with a standardized questionnaire. The results were mainly analyzed by descriptive measures. RESULTS: Twenty-two patients (age, 47.82 +/- 12.65 years) with adverse reactions to PLA were included. The most frequent adverse reaction was nodule formation found in all patients. In 13 (59.1%) of the cases, nodule formation was considered to be severe. Nodules appeared after a mean latency period of 6.00 +/- 5.84 months. The duration of the adverse reactions until the interview was 14.32 +/- 10.13 months. The frequency of patients with adverse events to PLA was found to decrease after new recommendations concerning the dilution of the product were launched. CONCLUSION: PLA is an injectable filler substance that may cause subcutaneous nodules in treated patients. Our data support a decreased risk of adverse reactions with an increased dilution. However, nodule formation still appears to be a characteristic feature of PLA.

Risk of severe adverse reactions to an injectable filler based on a fixed combination of hydroxyethylmethacrylate and ethylmethacrylate with hyaluronic acid.

BACKGROUND: Hydroxyethylmethacrylate and ethylmethacrylate in a fixed combination with hyaluronic acid has been used as an injectable filler for nearly a decade. Severe adverse reactions have been associated with this filler. OBJECTIVE: To characterize the adverse reactions to this filler. METHODS: Data from the Berlin registry for adverse reactions to injectable fillers were analyzed. The registry is a partially population-based registry with the aim of collecting adverse reactions to injectable fillers. Patients were interviewed based on a standardized questionnaire. RESULTS: Thirty-four of 118 (28.8%) registered patients were treated with this filler. Of 95 treated areas, 87 responded with a reaction (91.6%). The most frequently observed adverse events were the development of nodules (n=85) in 87 affected areas, discoloration (n=39), erythema or inflammation (n=32), and swelling (n=24). Most nodular reactions were rated as severe. The mean time after the last treatment until appearance of an adverse reaction was 23.1+/-22.8 months. CONCLUSION: Adverse reactions to this methacrylate filler are common. The mean latency period for these mostly severe rated reactions was nearly 2 years. Based on the frequency and severity of these reactions, the use of this filler does not seem to be advisable.

Native hyaluronic acid in dermatology--results of an expert meeting.

The glycosaminoglycan hyaluronic acid (HA) is a major component of the extracellular matrix of the skin and plays an important role in the metabolism of the dermis.HA is responsible for hydration,nutrient exchange and protects against free radical damage;via signaling pathways it is also involved in biologic processes like cell differentiation and motility. Native HA has been employed for several years to help the skin to regain elasticity,turgor and moisture. In a clinical study an increase in elasticity and turgor following repeated injections with HA could be demonstrated, but this treatment approach is discussed controversially. An expert conference took place to find a consensus regarding use, aims of treatment, indications and limitations of this therapy. The decisions of the expert meeting are presented in this report.

Risk profiles of different injectable fillers: results from the Injectable Filler Safety Study (IFS Study).

BACKGROUND: Injectable fillers are widely used in aesthetic medicine. Although most materials are considered to be safe, adverse events occur. Our knowledge on frequency and potential risk factors is limited. OBJECTIVE: The aim of this study was to describe adverse reactions to injectable fillers based on a partly population-based case series. METHODS: Dermatologists, plastic surgeons, and maxillofacial surgeons in Berlin were asked to report patients with adverse reactions. Additional patients were obtained from a private practice. A standardized questionnaire was used to assess all data. All data were analyzed by descriptive measures. RESULTS: Fifty-six patients (age, 48+/-11.2 (SD) years) who had been treated with nine different fillers were assessed. In 48 patients treated with only one filler, 167 areas had been treated. In 129 (77.3%) areas adverse reactions occurred 12.2+/-15.6 (SD) months after injection. Adverse reactions to biodegradable fillers occurred after 4.9+/-5.8 (SD) months, and reactions to nonbiodegradable fillers after 18.3+/-19.0 (SD) months (p=.005). As adverse events, continuing pain, swelling, nodules, pigmentation, abscess formation, and erythema were found. CONCLUSION: Adverse reactions can be documented for all injectable fillers. Time until reaction as well as type of reaction, however, vary between different fillers. Further research is necessary to evaluate potential risk factors.