Clinic Rev Allerg Immunol DOI 10.1007/s12016-012-8348-5

Late-Onset Inflammatory Adverse Reactions Related to Soft Tissue Filler Injections

Jaume Alijotas-Reig & Maria Teresa Fernández-Figueras & Lluís Puig

# Springer Science+Business Media New York 2013

Abstract An ever-increasing number of persons seek medi- immunogenic or that complications are very uncommon, un- cal solutions to improve the appearance of their aging skin or wanted side effects do occur with all compounds used. for aesthetic and cosmetic indications in diverse pathological Implanted, injected, and blood-contact biomaterials trigger a conditions, such as malformations, trauma, cancer, and ortho- wide variety of adverse reactions, including inflammation, pedic, urological, or ophthalmological conditions. Currently, thrombosis, and excessive fibrosis. Usually, these adverse physicians have many different types of dermal and subder- reactions are associated with the accumulation of large numb- mal fillers, such as non-permanent, permanent, reversible, or ers of mononuclear cells. The adverse reactions related to non-reversible materials. Despite the claims of manufacturers fillers comprise a broad range of manifestations, which may and different authors that fillers are non-toxic and non- appear early or late and range from local to systemic. Clini- cians should be aware of them since the patient often denies the antecedent of or is unaware of the material The contents of the manuscript have not been previously published and employed. Most of these adverse effects seem to have an are not being considered by any other journal elsewhere at this time. All authors agree with the contents of the article and also having their immunological basis, the fillers acting more as adjuvants than names included in the list of authors. All authors have contributed in as direct T-cell activators, on a background of genetic predis- the conception, acquisition, and interpretation of data, and revision of position. Their treatment has not been the subject of well- the manuscript. JAR and LP drafted the paper, and MFF built tables designed studies; management of both acute and systemic and figures. The authors also state that they do not have any commercial or any reactions is often difficult, and requires anti-inflammatory other type of interest that may have influenced the drawing up and the and occasionally immunosuppressive therapy. The clinical, results of this paper. pathological, and therapeutic aspects of inflammatory and J. Alijotas-Reig immune-mediated late-onset adverse reactions related to soft Ageing and Systemic Autoimmune Research Unit, tissue filler injections are thoroughly reviewed herein. Service of Internal Medicine-I, Aging Basic Research Unit, Molecular Biology and Biochemistry Research Centre . . . ’ Keywords Acrylamides Adverse reactions ASIA for Nanomedicine (CIBBIM-Nanomedicine), Vall d Hebron . . . University Hospital, Barcelona, Spain Dermal fillers Granuloma Methacrylate . Treatment J. Alijotas-Reig : M. T. Fernández-Figueras : L. Puig Department of Medicine, Universitat Autonoma, Barcelona, Spain

M. T. Fernández-Figueras Introduction Pathology Department, Trias i Pujol University Hospital, Barcelona, Spain An ever-increasing number of persons seek medical solutions for their aging skin for purely aesthetic and cosmetic indica- L. Puig Dermatology Department, Sant Pau University Hospital, tions or for diverse medical conditions. Only for aesthetic Barcelona, Spain reasons, more than 10 million fillers have been injected in the USA in 2009 according to the American Society of Aesthetic * J. Alijotas-Reig ( ) and Plastic [1]. Currently, physicians have many dif- Josep Ma. de Segarra, 2-F, 08190 Sant Cugat del Vallés, Barcelona, Spain ferent types of dermal and subdermal fillers, which may be e-mail: [email protected] classified according to their origin and average persistence in Clinic Rev Allerg Immunol

Table 1 Non-biological and biological dermal fillers

Expected Microscopic features permanence

Calcium hydroxylapatite (CaHA) Up to 6 months Clumping, migration, or granulomatous reaction containing basophilic round structures. Filler may persist longer than ordinary Carboxymethyl cellulose + polyethylene oxide Up to 12–18 months ND Hydroxyethyl methacrylate/ethyl methacrylate Very long Granulomatous reaction with many giant cells engulfing polygonal translucent structures Paraffin Permanent Foreign-body granulomatous reaction containing abundant vacuoles of large size Polyacrylamide hydrogel (PAAG) Very long Foreign body and palisading granulomatous reaction surrounding a large pool of basophilic foamy material with mucinous appearance Poly-alkyl-imide Very long Irregular encapsulation, dystrophic calcification, acute inflammation in relation to pools of alcian-blue-positive basophilic mucinous material Polydimethyl siloxilane (silicone oil) Permanent Clumping, migration, chronic inflammation, or granulomatous reaction with pseudoxanthomatous containing translucent particles of birefringent silicone Poly-L-lactic acid Up to 2 years Granulomatous reaction with multinucleated giant cells containing translucent spiculated polarizable aggregates Polymethylmethacrylate (PMMA) Up to 5 years Granulomatous reaction containing translucent medium-sized Polyethyl methacrylate (pHEMA-EMA) + hyaluronic round structures acid Poly-tetrafluoroethylene (PTFE)/expanded PTFE Permanent Migration. Acute inflammation with granulation tissue suggesting Polyvinylhydroxide microspheres in polyacrilamide Up to 9 months Granulomatous reaction containing translucent microspheres Polyvinil-pirrolydone + silicon Permanent Granulomatous reaction. Translucent yellowish spiculated or “popcorn”-shaped aggregates of particles Biological fillers Expected Microscopic features permanence Alginate 3 to 12 months Severe granulomatous reaction. The filler may not be visible or appear as large basophilic oval particles (0.1–0.12 mm) Up to 12 months Non-specific inflammation, foreign body reaction, or granuloma annulare-like reaction. Occasional necrosis. Characteristics of non-human collagen polarization differ from those of human collagen allowing its identification Dextranomeres + hyaluronic acid Up to 12 months Granulomatous foreign-body reaction surrounding spherical particles of dextrans, sometimes immersed in a hyaluronic acid mucinous background. In cases of delayed inflammatory reaction, only a non-specific chronic inflammation is observed Fat More than 2 years Fat necrosis, fibrosis, and dystrophic calcification Hyaluronic acid in different forms Up to 12 m Granulomatous reactions surrounding bluish translucent mucinous material corresponding to hyaluronic acid tissue [2, 3]. Besides, an increasing number of new dermal reversibility of their adverse effects. Over the last 10 years, fillers are currently available (Table 1). The properties of an different clinical profiles [7, 8] as well as suggestive histopath- ideal filler—mainly to be safe (neither allergenic nor immuno- ological patterns have been described [13, 14], and some genic), non-carcinogenic, non-teratogenic, and non-migratory authors have proposed a grading system classification of —are not entirely accomplished by any of the available materi- foreign body reactions induced by injected fillers into als. Even though manufacturers and different authors claim that four categories [15]. Implanted and injected biomaterials fillers are non-immunogenic or that complications are very trigger a wide variety of adverse reactions, including uncommon [4, 5], unwanted side effects do occur with all the inflammation, thrombosis, and fibrosis. Usually, these compounds used [6–14]. Thus, two notions are lacking in the adverse reactions are associated with the rapid accumu- commonly used classifications of fillers: long-term safety and lation of large numbers of mononuclear cells [16]. Clinic Rev Allerg Immunol

Fig. 1 Normal and pathological cell responses after foreign material injections in humans. a Normal events after filler injection. b Pathological events in late-onset inflamma- tory adverse reactions after fill- er injection

In this review, we will discuss the main clinical and classified according to their origin and average persistence pathological features of local and systemic late-onset ad- in tissue—resorbable, non-resorbable, or temporary, semi- verse reactions, including the histopathologic findings, permanent, and permanent [2, 3]. immunopathogenic basis, and therapeutic schedules related A non-comprehensive list of fillers ever used in soft to soft-tissue dermal filler injections. tissue augmentation is provided in Table 1, with detailed reference of their composition, brand names, permanence, source, types of adverse reactions reported, and histopatho- Search Strategy and Selection Criteria logical clues to their identification.

A comprehensive MEDLINE, PubMed, and Google Scholar electronic database search was performed (2000–January Late-Onset, Immune-Mediated Adverse Reactions 2012), which was restricted to papers published in English, Related to Fillers using the relevant key words: dermal fillers, soft tissue filler, injectable filler, tissue augmentation, hyaluronic acid, collagen, Immune-Mediated Delayed Local Reactions poly-L-lactic acid, hydroxylapatite, methacrylate, silicone, pol- yalkylimide, polyacrylamide, biofilm, granuloma, ASIA, auto- Non-permanent Fillers immune diseases, adverse reactions, and treatment. Selected articles published before 2000 referring to gen- Alijotas-Reig et al. [7] reported a series of 25 patients eral concerns regarding to the studied topic were also in- with delayed hypersensitivity reactions following injec- cluded. Bibliographies of the retrieved articles were also tions of fillers containing hyaluronic acid, alone or com- scanned and searched manually for relevant papers. The bined with acryl hydrogel. The average latency time was initial search provided almost 300 articles. Finally, only 14 months; six patients had recurrent bouts. Even though 72 studies were selected and included. some fillers are able to perpetuate chronic granulomatous inflammation around the , bacterial colonization may also cause a chronic inflammatory reaction, and late Types, Classification, and Characteristics appearance of inflammatory nodules and abscesses of the Most Common Injectable Dermal Fillers should be treated initially with empiric antibiotic treat- ment [17]. If there is fluctuation, bacteriological, myco- Currently, many different types of dermal and subdermal logical, and mycobacteriological cultures should be done, fillers have been launched to the market, which may be and if there is no clinical improvement after 1 week, Clinic Rev Allerg Immunol biopsy specimens should be obtained for histopathologi- [28, 29]. They develop suddenly many years after the cal examination and microbiological cultures. injection, with redness and swelling of multiple areas of Product-related injection site nodules, typically 5 mm firm, fixed but rather soft nodules, not very painful but or less in diameter, have been commonly seen with associated with local lymphadenopathy [30]. poly-L-lactic acid, particularly in the human immunode- Development of hard and persistent facial with ficiency virus (HIV)-infected population. [18]. Poly-L- exacerbations and remissions, followed by local subcutane- lactic acid-induced nodules and foreign-body granulo- ous nodules, has been recently reported 1 to 48 months post- mas may be difficult to treat [19] and may become injection [31]. persistent and associated with a systemic granulomatous disorder [10]. Systemic Adverse Reactions

Permanent Fillers Late-Onset Distant and/or Systemic Inflammatory, Immune-Mediated Reactions Late-onset granulomatous reactions and nodules are much more frequent after treatment with permanent filler materi- Silicone injections, mainly silicone breast augmentation als; they can appear 1 to 2 years after treatment with poly- prosthesis, have been related to diverse autoimmune sys- methylmethacrylate microspheres or methacrylate fillers temic diseases (ASD) especially systemic sclerosis (SS), [20]. Granulomas following injection of bovine collagen inflammatory myopathy, rheumatoid arthritis, adult Still plus polymethylmethacrylate (Artecoll®) are rare (0.01 % , mixed connective tissue disease (Sharp disease), of patients) and often appear after the second or third im- eosinophilic fasciitis, overlap SS/SLE, and fibromyalgia plantation of product; half of the patients experiencing them [32], or with unspecific or undifferentiated connective- report an associated severe infection (influenza) or some tissue diseases [33]. Even though case reports are con- type of facial injury [20]. This might be explained by in- tinuing to be reported, well-designed epidemiological creased serum levels of interferon [21]. studies have failed to demonstrate a true relationship Polyacrylamide differ in molecular weights, water between silicone injections and ASD [34]. To avoid the content, and viscosity, which may affect their complica- local and systemic side effects related to silicone liquid tion rates. Aquamid® (2.5 % polyacrylamide and 97.5 % or fluid, “bag-gel” bioimplants were introduced, mostly water) is often associated with the formation of granulo- for breast or buttock augmentation. However, leakage of mas [22]. Injections of polyalkylimide filler have also silicone may also occur through these bags, either by been associated with delayed complications including diffusion or after trauma. In any way, silicone gel is abscess formation, migration of filler, recurrent swelling, capable of migrating to distant sites, where it may pro- and inflammatory nodules in up to 5 % of treated voke inflammatory reactions [35]. Multiple distant in- patients [8, 23]. Puncture of old (6 months to 4 years) flammatory nodules and panniculitis have also been polyacrylamide gel implants has been associated with described with silicone filler injections [36], especially acute inflammation and significant induration of the in dependent areas when silicone had been injected in corresponding areas in a series of 12 patients, in which the buttocks, thighs, or calf. cultures of removed gel were negative [24]. Late-onset inflammatory nodules have been reported fol- Liquid silicone was widely used in Europe and Japan lowing calcium hydroxylapatite injections both “in situ” and in the 1940s, and became popular in the USA in at a distance from the site of injection [37]. Axillary lymph- the 1950s and 1960s when large volumes of material— adenitis related to polyacrylamide gel breast augmentation commonly admixed with olive oil—were injected, result- has also been reported [38]. Distant panniculitis of thighs ing in permanent deformities and often disastrous, even and buttocks, biopsy proven, extensive livedo reticularis, fatal, complications [25]. Increasing demand of perma- sicca syndrome, and human adjuvant disease (HAD) have nent fillers and the introduction of the microdroplet tech- been described in patients subject to polyalkylimide gel nique has led to a revival of medical-grade silicone gels injections [8]. and their off-label use in cosmetic surgery; when used in Generalized skin rash, sicca syndrome, sarcoid-like small amounts for augmentation, they seem to yield a reactions, and cutaneous vasculitis [7, 39]havebeen low rate of foreign-body granulomas [26]. Silicone fluid related to several implant fillers other than silicone stimulates a very thin-walled fibrous capsule so that injections, such as polyalkylimide, methacrylate, and displacement by gravity along fascia and muscle planes hyaluronic acid. Interestingly, to the best of our knowl- can occur [27]. Late sclerotic reactions can develop edge, only polyacrylamide implants have been related to around free silicone oil, and the typical features of soft exacerbations or bouts of inflammatory bowel diseases silicone foreign body granuloma are well characterized in patients already diagnosed as having either ulcerative Clinic Rev Allerg Immunol

Table 2 Systemic reported complaints and/or diseases relat- Complication Silicone PAI PA MTC HA PLA Collagen HAP ed to most common injectable fillers Flu-like symptoms + −−− −− + − Lymphadenitisa + − + −−−+ − Pneumonitis + −−− −− − − NTPE + −−− + −− − Serositis + − + − + −− − Hepatitis + −−− −− − − Panniculitis + + − + −− + − AHS acute hypersensitivity syn- Angioedema + + + + + + + − drome type I, Collagen non- Bone erosion + −−− −− − − human-based collagen, ASIA −−− −− − − Autoimmune/auto-inflammatory Amyloidosis + Syndrome Induced by Adju- Siliconosis + −−− −− − − vants, HA animal- and non- AHS −−−++− + − animal-derived hyaluronic acid Distant nodules + + − + − ++ + compounds, HAD human adju- vant disease, HAP hydroxylapa- Renal failure + −−− −− − − tite, MTC methacrylate HAD + + − + −− − − — compounds polymethylmetha- UCTD + −−− −− − − crylate and ethylmethacrylate, − −− − NTPE non-thrombotic pulmo- Sarcoidosis + + + + nary embolism, PA polyacryl- Sclerodermia + −−− −− − − amide, PAI poly-alkyl-imide, Inflammatory myopathy + −−− −− + − PLA poly-L-lactic acid, Sarcoid- Sjögren syndrome + + − ++−− − osis sarcoidosis and sarcoid-like −−−− −− − granulomatous diseases, UC ul- Vasculitis + cerative colitis, UCTD undiffer- Bouts of UC −−+ −−−− − entiated connective tissue Fibromyalgia + −−− −− − − disease Hand’s erythemab ++++++−− aNon-infectious origin ASIA + + + + + + −− bVasculitis-like type colitis or mainly Crohn disease [40]. A relationship between Pathogenesis bovine collagen and inflammatory myositis has also been reported [41](Table2). Inflammation around an implant material is normal (Fig. 1 Shoenfeld et al. [42] recently coined the term Auto- top) and always occurs, and eventually leads to its reabsorp- immune/auto-inflammatory Syndrome Induced by Adju- tion in the case of biodegradable volumizers, which are vant (ASIA) for an umbrella entity that included those expected to be immunologically inert and stimulate collagen cases of diverse clinical signs and symptoms, together neogenesis [44]. Phagocytosis is the normal tissue reaction to with some laboratory markers related to inflammation or any foreign body and appears to be the single most important autoimmunity. A common denominator to this syndrome factor in determining the longevity of the fillers [45]. Particles is the exposure to a component that comprises an adju- larger than 5 μm generally require aggregated macrophages vant effect (i.e., infection, vaccination, and bioimplant). (foreign-body giant cells) to be phagocytosed, and particles Another common characteristic is the co-exposure to larger than 15 to 20 μm are generally not subject to ingestion more than one trigger, such as the exposure to another by macrophages and transportation to the local lymph nodes deleterious environmental factor (i.e., infectious agent or [46]. Particle shape and physical properties of the particles biopolymers). Like this, we have recently communicated may play a larger role in phagocytosis than mere size since a series of patients injected with diverse fillers other macrophages seem to have become evolutively specialized in than silicone, i.e., hyaluronic acid compounds, acryla- recognition of bacterial pathogens [45]. mides, and methacrylate compounds, which fulfill the ASIA suggested classification criteria [43]. Filler-Related Granuloma Formation Thus, most systemic forms of immune-mediated compli- cations related to modern human fillers may share clinical The failure of effective phagocytosis leads to granuloma for- and laboratory characteristics included in the proposed mation, with aggregates of activated macrophages assuming ASIA category. an epithelioid morphology, giant cells of different types, and a Clinic Rev Allerg Immunol

Fig. 2 Sequence of pathogenetic events leading to granuloma forma- into a full-blown disease. Fillers may also elicit an APC-mediated tion and reactivation of inflammatory response. Circulating granulo- adaptive immune response. The failure of effective phagocytosis leads cytes move into the soft tissue and are the first line of defense. to granuloma formation, with aggregates of activated macrophages Monocytes differentiate into macrophages that eventually become the assuming an epithelioid morphology, giant cells of different types, dominant cell type. Fillers may act as adjuvants and increase innate and a surrounding infiltrate of T lymphocytes that secrete cytokines immune responses by mimicking evolutionary conserved molecules, such as tumor necrosis factor (TNF) alpha, interferon gamma, and IL- for instance bacterial wall components or unmethylated CpG-DNA 12, responsible for ongoing macrophage activation and inflammatory residues, and binding to Toll-like receptors (TLRs); they also enhance cell recruiting. Eventually, the granuloma becomes surrounded by a the activities of antigen-presenting cells (APCs).The adjuvant effect of fibrotic rim and, in the case of , the center becomes necrotic. fillers and microbial molecules (in the case of superinfection), namely Some biomaterials would affect the immune response acting as adju- the non-antigenic activation of the innate and regulatory immunity, as vants rather than as antigens by themselves. In several cases of filler- well as the expression of various regulatory cytokines, may determine related adverse effects, triggering factors may be found, mainly local if an inflammatory/autoimmune response remains limited or evolves trauma, infections, or vaccines surrounding infiltrate of T lymphocytes that secrete cytokines prostheses when certain bacteria in exudates settle to a smooth such as tumor necrosis factor (TNF) alpha, interferon gamma, artificial surface and develop a polysaccharide biofilm that and IL-12, responsible for ongoing macrophage activation protects them from disinfectants and antibiotics, but evidence (Fig. 1 bottom and Fig. 2). An acute inflammatory process for their role in late reactions to fillers other than shelled involving a quiescent granuloma years after the injection silicone implants is far from settled [47, 48]. might be related to the development of bacterial biofilms or structured colonies of microorganisms encapsulated in an Adjuvants, Toll-Like Receptors, Immune Response, extracellular matrix that can surround a foreign body and and Granuloma can lead to a low-grade chronic infection with eventual spon- taneous or injury-mediated reactivation. The role of biofilm Bioimplants have been postulated to act as T-cell-specific acti- infections is indisputable on inert surfaces such as teeth, vators, either directly or through the Toll-like receptors; they catheters, breast implants, and artificial hip and knee joint might rather act as adjuvants in individuals with predisposing Clinic Rev Allerg Immunol

Fig. 3 a A large nodular aggregate of bovine collagen can be identi- by a granulomatous infiltrate in a reaction to the Outline®. e Transpar- fied in the . The polarizing properties are different from those of ent accretion of Bioplastique® recognizable by its spiky contour sur- human collagen, facilitating its identification. b Blue spheres of dex- rounded by a dense neutrophilic infiltrate and a peripheral palisade of tranomeres and a background of bluish hyaluronic acid that is the macrophages. f Microvacuolated macrophages resembling lipoblasts hallmark for Matridex® allow its recognition. In this case, an intense intermixed with adipocytes due to an old silicone infiltration and granulomatous reaction, rich in multinucleated giant cells, is present. c accumulation of homogeneous pale blue hyaluronic acid in the upper Polygonal translucent particles of methacrylate engulfed by foreign part of the image, in a biopsy specimen of an injection-triggered body giant cells. d Bubbly collections of blue substance surrounded lymphohistiocytic inflammatory reaction genetic background. Recently, we have demonstrated the adju- receptors (TLRs) with further release of inflammatory cyto- vant role played for silicone [49], hyaluronic acid compounds kines from T-helper and mast cells [51]. TLR expression, in [50], and acrylamides (Alijotas-Reig, unpublished results). several different cell types, and the active cross-talk that Thus, some biomaterials would affect the immune response antigen-presenting cells and B cells display with T cells may acting as adjuvants rather than as antigens by themselves. explain why these receptors are now accepted as a link be- In several cases of filler-related adverse effects, triggering tween adaptive and innate immunity [51, 52]. factors may be found, mainly infections or vaccines [8, 12, 14]. The adjuvant effect of microbial molecules, namely the Adverse Reactions Caused by Subsequent Injections non-antigenic activation of the innate and regulatory immuni- of Different Fillers ty, as well as the expression of various regulatory cytokines, may determine if an inflammatory response remains limited or The possible increased risk of adverse reactions related to evolves into a full-blown disease. Adjuvants increase innate consecutive injections of different fillers in the same region immune responses by mimicking evolutionary conserved has been suspected on clinical grounds [7, 53]. Bachmann et molecules, for instance bacterial wall components or unme- al. [53] did not find evidence that consecutive injections thylated CpG-DNA residues, and binding to Toll-like increased the risk of adverse reactions, especially in the Clinic Rev Allerg Immunol cases of biodegradable fillers. In our review of 260 cases Treatment of Late-Onset Adverse Immune-Mediated suffering from filler-related reactions, we found that repeat- Reactions Related to Fillers ed injections of different fillers in the same region or in different sites do not increase the risk of adverse reactions; Local/Topical Treatments nevertheless, when they appeared they were more likely to become chronic and more severe [7, 54]. The location of the inflammatory reactions induced by filler injections, usually subcutaneous, makes them rather unsuit- Histopathological Evaluation of Implant Filler Reactions able for a topical therapeutic approach. Despite that fact, (Fig. 3) diverse drugs have been used with variable success. The usual first step in the treatment of local inflammatory Most filler reactions share many histopathological features, nodules includes local injection of fluorinated corticoste- such as an inflammatory process involving the dermis and roids, mainly triamcinolone acetonide and betamethasone subcutaneous tissue, containing predominantly T lympho- [2, 7–9, 59]. This treatment is useful in those cases with cytes, most of them CD4+, and a smaller population of B few and small inflammatory nodules. Some authors use a lymphocytes. Macrophages tend to be abundant, often engulf- 1:1 mixture of fluorinated corticosteroids with 5-fluouracil ing or surrounding particles of the injected material. Macro- or bleomycin [2, 7–10, 59]. Since repeated injections are phages can adopt several patterns including lipogranulomatous usually required, they should not be done too superficially reaction, palisading of epithelioid cells, or a giant cell foreign- in order to avoid skin atrophy. Other potential complications body reaction. Eosinophils are usually present in a varied related to repeated local injections of corticosteroids are skin proportion. Collagenization with scant fibroblastic prolifera- discoloration and infection. Hyaluronidase, an enzyme that tion appears at an early stage and can extend to deep tissues degrades hyaluronic acid of all known sources, has been including the striated muscle, particularly around the and proposed to treat hyaluronic-acid-related granulomas. Its eyes, where fibers of striated muscle are more superficial. efficacy has been reported in some cases [60]. Other authors Dystrophic calcification is another complication of this inflam- advocate for a reconsideration of hyaluronidase use because matory process. Some biopsies contain large areas of abscessi- of the potential induction of hypersensitivity-mediated local fication with necrosis, ulceration, and fistulization. or generalized reactions [61]. Conversely, other microscopic features depend on the type Imiquimod activates immune cells through the Toll-like re- of implanted material, and they can be distinctive enough to ceptor 7 (TLR7) and induces secretion of cytokines primarily allow its identification (Table 1). Autologous fat implantation interferon-α, interleukin-6 (IL-6), and TNF-α. Anecdotal can be the cause of an intense lipogranulomatous reaction reports of granuloma related to filler injections treated with [55]. Paraffin oil, long time out of use, produces round, wide imiquimod 5 % ointment have been published [62]. Considering spaces of different sizes (“Swiss cheese” pattern). Bovine the balance between the potential side effects and its effective- collagen is typically surrounded by a foreign body, necrobiotic ness, imiquimod use cannot be recommend in this field. granuloma, or sarcoid-like granulomatous reaction [56]. The Calcineurin inhibitors inhibit both T-lymphocyte signal implanted collagen differs from native collagen by its texture transduction and IL-2 transcription and production. Few and polarized light properties [57]. Medical-grade silicone can authors have used topical preparations of tacrolimus 0.1 % be identified inside macrophages as translucent birefringent twice a day and pimecrolimus 1 % twice a day for the diminutive droplets (lipoblast-like cells); rarely larger treatment of corticosteroid-“resistant” small and superficial amounts are surrounded by a thick collagen capsule caus- granulomas, usually reporting good responses [2, 63]. ing a complication that is known as “beading” [58]. HA- derived dermal fillers appear as aggregates of light blue Systemic Treatments material surrounded by a palisade of foreign-body-type multinucleated giant cells. Alcian blue or colloidal iron Oral corticosteroids are the most used systemic treatment for staining may confirm the nature of this material. Perma- filler-induced adverse reactions. To the best of our knowledge, nent, long-, and medium-lasting fillers are more suscepti- no refractory cases have been reported when using medium– ble to cause foreign-body granulomatous reactions high doses of prednisone (0.5 to 1 mg/kg/day) [2, 7–10]. Given surrounding the injected material, which can be recog- the chronic nature of these pathological reactions, physicians are nized by their microscopic peculiarities [14, 28, 29]. Fi- often forced to maintain corticosteroid therapy over time. Thus, nally, some patients carry more than one filler injected at the potential for systemic adverse effects related to corticosteroid different times. Not infrequently, permanent filler that has treatment should not be underestimated. In these cases, combi- remained asymptomatic for many years can start a reac- nation treatment with a second or even a third drug is recom- tion after the local injection of a second material, and both mended in order to be able to taper down or minimize the dose fillers can be identified in the same microscopic field. of corticosteroids. Different drugs have been tried with this Clinic Rev Allerg Immunol purpose, but no well-designed studies on the effectiveness of taking into account the therapeutic profile of these drugs [69]. these therapeutic schedules have been reported. TNF alpha blockade has an inhibitory action on macrophages, Antimalarials, mainly hydroxychloroquine, are used which may lead to granuloma disruption and theoretically based on the same rationale as in other granulomatous or increase the risk of disseminated infections due to intracellular autoimmune diseases. Antimalarials have many anti- granuloma-forming microorganisms. Some cases of granulo- inflammatory and immunoregulatory properties, particularly matous reactions to dermal fillers, especially those caused by inhibiting phospholipase activity and blocking production silicone, and methacrylate compounds or combinations of of several pro-inflammatory cytokines. Cases of granuloma- different fillers can be notoriously difficult to treat, and anti- tous reactions secondary to implant fillers have been treated TNF drugs were initially tried as a last resort. Several authors with hydroxychloroquine, at doses ranging from 4 to have reported good responses following their use, but at least 6.6 mg/kg/day, usually with acceptable results and a one author has found the opposite effect with etanercept—the corticosteroid-sparing effect [7–10]. Its therapeutic effect formation of granulomas in a patient after starting the drug often takes 4 to 6 weeks to appear. [70]. According to the possible severe side effects, further Antihistamines, blocking H1 and H4 histamine receptors, research is needed to determine the true benefit risk ratio of may exert anti-inflammatory and immunoregulatory actions this family of immunomodulating drugs. [64], particularly inhibiting the expression and production of Even though no well-designed clinical trials that may intercellular adhesion molecule 1 (ICAM-1), IL-4, IL-6, and support this practice have been published to date, several IL-12, and also inhibiting Toll-like receptor 3 (TLR3) ex- combinations of systemic drugs other than corticosteroids pression. Thus, there seems to be some rationale behind the have been proposed for the treatment of the most severe, use of antihistamines for the treatment of those adverse recurrent, extensive, or systemic cases. reactions. At any rate, they might deserve therapeutic trial in association with other drugs. Surgical Options Allopurinol has been used for the treatment of cutaneous sarcoidosis and in granuloma related to implant fillers, usually In selected cases, surgical procedures are necessary to elim- at high dose (450–600 mg/day) with occasional success [2, inate granulomatous reactions. Likewise, only 10 % of cases 65], particularly in patients having undergone prior injections belonging to The Therapy of Adverse Reactions of Inject- of silicone. Considering multiple potential side effects of this able Fillers (TARIF) Study [71] were subject to a surgical drug, caution should be exercised before its use is planned. intervention. During active inflammatory processes or when According to reports of Christensen et al. [14, 40], anti- patients have large and/or multiple lesions, surgical proce- biotics have been used for the treatment of these reactions dures should be avoided because of the risk of filler migra- related to fillers, even though the evidence for a causal role tion, infection, formation of fistulae, persistent granulation of bacterial infection injections in granulomatous responses is tissue, marked deformities, scars, and appearance of new inconclusive. Isolated antibiotic treatment has not been effec- inflammatory bouts related to injury [7, 8]. Thus, only a few tive in our own experience [7–10]. In cases where antibiotics and selected cases should undergo surgical procedures. seem to be useful, it is unclear whether the improvement might be related to their bactericidal properties or to their anti- inflammatory and/or immunomodulating effects [7, 14, 66]. Areas of Uncertainty Colchicine has been claimed to be effective in the manag- ing of filler-induced granulomas [67], but reports on its pos- Only a few cases of injected people will develop late-onset sible therapeutic effect in filler-induced granuloma are scarce. inflammatory granuloma. Thus, to think that a specific genetic Thus, a formal recommendation for its use cannot be done. background should exist has a rationale. The role played by Cyclosporin A has been used in a few cases of granuloma microbes directly or through its adjuvant capability has to be related to filler injections [2, 68]. Alijotas-Reig et al. [36] accurately studied. A state-of-the-art review on facial soft- reported good responses in a series of patients with delayed tissue fillers has been recently sponsored and published by adverse reactions to fillers that were refractory to other the American Academy of Dermatology [72]andtheAmer- commonly used drugs and who were treated with tacrolimus ican Society of Plastic Surgeons. However, neither all the at low doses. Interestingly, no valuable side effects related to currently existing fillers nor all the published articles have tacrolimus appeared. In daily clinical practice, tacrolimus been collected systematically, and the information provided in appears to be useful in the treatment of this kind of patients. these conference proceedings is focused on the available Tumor necrosis factor inhibitors (anti-TNF) block circulat- evidence on the effectiveness of facial fillers and, to a lesser ing and/or cell bound TNF. Interestingly, anti-TNF drugs may extent, the early or short-term complications, rather than the cause a wide range of immunologically mediated reactions, inflammatory and more severe late-onset adverse effects. Al- sarcoidosis included, which can be considered as paradoxical so, no information about long-term follow-up and treatments Clinic Rev Allerg Immunol has been included. Thus, and unfortunately, according to 5. Andre P, Lowe NJ, Parc A, Clerici TH, Zimmermann U (2005) the current available data, evidences and recommenda- Adverse reactions to dermal fillers: a review of European experi- – tions on the diagnostic procedures and subsequent ther- ences. J Cosmet Laser Ther 7:171 176 6. Bergeret-Galley C (2004) Comparison of resorbable soft tissue apeutic schedules regarding adverse reactions induced fillers. Aesthetic Surg J 24:33–46 by fillers do not exist. 7. Alijotas-Reig J, Garcia-Gimenez V (2008) Delayed immune- mediated adverse effects related to hyaluronic acid and acrylic hydro- gel dermal fillers: clinical findings, long term follow-up and review of the literature. J Eur Acad Dermatol Venereol 22:150–161 Conclusions 8. Alijotas-Reig J, Garcia-Gimenez V, Schwartz SJ (2008) Late-onset immune-mediated adverse effects related to polyalkylimide dermal An ever-increasing number of people are currently using fillers. Arch Dermatol 144:637–642 dermal fillers. Physicians have access to many types of dermal 9. Alijotas-Reig J, Garcia-Gimenez V, Miró-Mur F, Vilardell-Tarrés M (2009) Delayed immune-mediated adverse effects related to and subdermal fillers, which may be classified according to polyacrylamide dermal fillers: clinical findings, management, and their origin and average persistence in tissue. Up to now, all follow-up. Dermatol Surg 35:360–366 known fillers launched have been shown to be able to provoke 10. Alijotas-Reig J, Garcia-Gimenez V, Vilardell-Tarres M (2009) late-onset adverse effects. Their true prevalence is unknown Late-onset immune-mediated adverse effects after poly-L-lactic acid injection in non-HIV patients: clinical findings and long- but appears to be significant according to the huge amounts of term follow-up. Dermatology 219:303–308 published manuscripts and consensus conferences. The ma- 11. Descamps V, Landry J, Francés C, Marinho E, Ratziu V, Chosidow jority of the late-onset adverse effects are inflammatory and O (2008) Facial cosmetic filler injections as possible target for immune-mediated in nature. Edema, granulomas/inflammato- systemic sarcoidosis in patients treated with interferon for chronic hepatitis C: two cases. Dermatology 217:81–84 ry nodules, sarcoid-like disorders, and panniculitis are the 12. Hirsch R, Stier M (2008) Complications of soft tissue augmenta- findings most commonly seen. Rarely, systemic granuloma- tion. J Drugs Dermatol 7:841–845 tous and autoimmune diseases, including ASIA, can be seen. 13. Requena C, Izquierdo MJ, Navarro M, Martinez A, Vilalta JJ, All patients should undergo to a complete medical history and Botella R (2001) Adverse reactions to injectable aesthetic micro- implants. Am J Dermatopathol 23:197–202 physical examination, blood tests, imaging studies, and cul- 14. Christensen L, Breiting V, Jansen M, Vuust J, Hogdall E (2005) tures of skin or extruded/aspirated material when necessary. Adverse reactions to injectable soft tissue permanent fillers. Aes- Either cutaneous lesions or nodule biopsy is advised but not thetic Plast Surg 29:34–48 mandatory. From a therapeutic perspective, intralesional cor- 15. Duranti F, Salti G, Bovani B, Calandri M, Rosati M (1998) Inject- able hyaluronic acid gel for soft tissue augmentation. Dermatol ticosteroids must be the first line of therapy. 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