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Delayed Immune-Mediated Adverse Effects Related to Polyacrylamide Dermal Fillers: Clinical Findings, Management, and Follow-Up

´ JAUME ALIJOTAS-REIG, MD, PHD,Ãy VICTOR GARCIA-GIMENEZ, MD,yz FRANCESC MIRO-MUR, PHD,z AND Ãy ´ MIQUEL VILARDELL-TARRES, MD, PHD

BACKGROUND It has been thought that polyacrylamide (PA) injections do not have inflammatory side effects. Recent evidence shows that local and regional delayed adverse effects may appear with its use. OBJECTIVE To evaluate the clinical complaints and follow-up of patients with delayed immune-mediated adverse effects related to PA injections. METHODS Prospective, case-series study of 10 patients with delayed adverse effects related to PA injections. Only patients with intermediate or delayed adverse effects related to polyacrylamide injection were included. Patients with immediate side effects were excluded. Patients underwent clinical management, follow-up, and when possible, blood tests and biopsy. RESULTS Average latency period to onset of symptoms was 10 months (range 2–36). Tender, inflammatory nodulesFgranulomasFwith pseudo-abscesses were commonly seen. Laboratory abnormalities were found in all analyzed cases. After 20.1 months average follow-up, five patients were in remission, two had recurrent bouts, and three were lost to follow-up, one of them in remission. CONCLUSION Although it happens infrequently, local and regional delayed and recurrent granulomatous reactions may complicate PA gel injections. The authors have indicated no significant interest with commercial supporters.

ore and more people are seeking medical solutions for their aging skin or for purely esthetic and cosmetic indications. Currently, physicians have many different types of dermal and subdermal fillers, including nonpermanent, permanent, reversible, and nonreversible materials.1,2 Different classes of fillers have been proposed, according to their origin and longevity (duration).1,2 Although manufacturers and different publications claim that the fillers are nontoxic and nonimmunogenic and that complications are uncommon,3,4 unwanted side effects occur with all compounds used.1,5–7 Thus, two notions are lacking in the usual classes of dermal fillers used: long-term safety and the reversibility of side effects. At present, acrylamide compounds, mainly polyacrylamide (PA), are increasingly used in

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Europe. PA gel (Aquamid Contura International, Soeborg, Denmark) is a gel polymer made of PA (2.5%) and water (97.5%).8 Although in the early reports on PA injections for cosmetic purposes no significant signs of bio-incompatibility were reported,9–12 more recent evidence refutes these statements, and the complete safety of PA gels can therefore no longer be corroborated.1,7,13–16 We communicate herein our experience with a cohort of 10 patients who were referred to our immunology unit presenting with delayed adverse reactions related to PA implant fillers.

Patients and Methods In recent years, a prospective protocol has been established to manage patients with intermediate and

Vall d’Hebron University Hospital, Barcelona, Spain; yDepartment of Medicine, Autonomous University of Barcelona, Barcelona, Spain; yEuropa Medical Centre, Barcelona, Spain, Spain; and zSpanish Society of Medicine and Cosmetic Surgery, Barcelona, Spain
& 2009 by the American Society for Dermatologic Surgery, Inc.  Published by Wiley Periodicals, Inc.  ISSN: 1076-0512  Dermatol Surg 2009;35:360–366  DOI: 10.1111/j.1524-4725.2008.01041.x
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ÃDepartment of Internal Medicine I and zLaboratory Unit, Aging Research and Systemic Autoimmune Diseases Unit,

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long-term side effects related to implant fillers, PA gel included. In all cases, physicians who work in esthetic and plastic clinics in different cities of Spain injected the fillers. Our Clinical Immunology Unit and members of the scientific committee of the Sociedad Espanola de Medicina y Cirugıa Cosmetica ˜ ´ ´ (Spanish Society of Cosmetic Medicine & Surgery) jointly designed this study protocol. Members of this society were invited to voluntarily send us all patients with intermediate or delayed side effects related to cosmetic and esthetic implant fillers. In accordance with the habitual protocol related to injection fillers, strictly sterile techniques were used in all cases. In all 10 analyzed cases, PA was injected accurately and in the recommended facial areas. Intermediate side effects were defined as the onset, between 1 and 12 months after bioimplants were filled, of one or more of the following clinical signs: edema, angioedema, skin induration, and swelling or tender nodules with or without fistulization or discharge of pus or filler material. Systemic complaints included fever, arthralgia, arthritis, skin lesions, dry eyes and mouth, and any other sign or clinical complaint, depending on the organ involved. Delayed side effects were defined as onset 12 months or longer after the filler injection, with the same local or systemic complaints referred to above. Up to July 2007, more than 150 cases of intermediate or delayed implant filler-related adverse effects had sought medical attention in our unit. Ten cases of adverse effects related to PA were recruited according to the above-mentioned criteria. Five cases were evaluated only through the review of their medical records, sent to us by their attending physician. Some of the cases were attended once in our outpatient clinic. Recommended clinical study protocol included standard blood test, C-reactive protein (CRP), fibrinogen, calcium, lactic dehydrogenase (LDH), angiotensin-converting enzyme (ACE), serum protein electrophoresis, antinuclear antibodies, and CH50. Biopsy of lesions was not mandatory but warranted. Treatment was based on antibiotics; nonsteroidal anti-inflammatory drugs

(NSAIDs), especially ibuprofen; local steroids; and oral prednisone; and in some cases, hydroxychloroquine or allopurinol.

Results Medical records of 10 patients were sent to us because nonimmediate side effects were suspected to be related to PA. Five cases were evaluated only through a revision of their medical histories sent to us by their attending physician. Five cases were also referred to our unit to undergo a complete study and follow-up. Nine of the ten cases were filled with PA alone. The age, sex, time lapse, previous implants, and main location of fillers may be seen in Table 1. All patients were evaluated during the active phase (while the side effect was clinically apparent). In all cases, a physician had filled PA. All of the cases were women. The average latency time between the PA filler implant and the onset of symptoms was 10 months (range 2–36). One case (number 2) had probably been previously filled with hyaluronic acid 36 months earlier, with no side effects detected. In all cases, PA had been injected in various zones of the facial area (Table 1). Predisposing conditions and triggering events in this series of patients may be seen in Table 2. Main complications can be seen in Table 3. In brief, painful inflammatory nodules of different sizes (0.5–4 cm in diameter) were seen. In cases 2, 3, 5, and 8, pseudo-abscesses appeared. Drainage and irrigation was performed repeatedly, and the material obtained was cultured, generally with negative results. Microorganisms were yielded in only one case (case 3) after multiple cultures. It was positive for gram-positive cocci. Polymerase chain reaction– DNA analysis was performed in cases 3 and 5, with negative results. Severe localized or generalized facial edema was present in two cases (cases 2 and 4). No systemic or distant manifestations were observed in any of the 10 cases. Laboratory Results Laboratory tests were done on four of the 10 cases (cases 2, 3, 5, and 9) (40%). Six patients refused.

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TABLE 1. Gender, Time Elapsed, Previous Implants and Location of Fillers in This Series
Patient 1 2 Age/Sex 35/F 42/F Latency 36 6 Previous Fillers No Probably hyaluronic acid 3 years before polyacrylamide was injected No No No No No No No No Main Location Glabella nasolabial folds Lips and cheeks

3 4 5 6 7 8 9 10
F = female.

49/F 50/F 55/F 49/F 54/F 34/F 51/F 43/F

3 2 2 2 24 12 12 3

Peri-ocular lines Lips and nasolabial folds Lips, cheeks, and nasolabial folds Glabella and lips Nasolabial folds and lips Glabella and peri-ocular line Cheek bones and nasolabial folds Cheek bones

Abnormalities in acute phase reactantsFCRP, fibrinogen, hypera-2, or gammaglobulinemia or a combination of some or all of theseFwere present in all four (100% of analyzed cases), high levels of ACE in three (75%: cases 1, 3 and 8), and LDH in one (25%: case 3). Complement proteins also showed low levels in one case (case 3), and antinuclear antibodies were negative in all cases. Serum calcium levels were within the normal range in all cases. Punch biopsy was performed on three patients (cases 2, 3, and 5). Histopathologic examination was similar in these three cases, showing a foreign-bodytype granuloma. No microorganisms were observed.

Therapeutic Schedule Although there was no bacterial growth, initial antibiotic treatment was assayed, as suggested by Christensen and colleagues.8,16 The antibiotics and doses used are shown in Table 3. Briefly, seven cases (70%) were placed on antibiotic treatment. Amoxicillin–clavulanic acid 875/125 mg three times a day and ciprofloxacin 500 mg twice a day were the antibiotics used in our cases. The length of treatment was 4 weeks. A response was obtained in only one case and was temporary. Nine of the ten patients were treated with NSAIDs, generally ibuprofen

TABLE 2. Predisposing Conditions and Triggering Events in This Series of Patients
Autoimmune Patient 1 2 3 4 5 6 7 8 9 10 Smoking No No Yes No No No Yes No No Yes Personal Noà No No No No Type 1 diabetes mellitus No No No No Background Familial No No No No No No No ND No ND Physician Physician Physician Physician Physician Physician Physician Physician Physician Physician Setting Triggering Events Trauma Yes No ND No No No ND ND No ND Infection No no ND No Yes No ND ND Yes ND

ÃAtopy. ND = no data.

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TABLE 3. Main Complications, Type of Treatment and Follow-Up
Patient 1 2 3 4 5 6 7 8 9 10
y z

Main Complication Inflammatory nodules skin induration, cyst Inflammatory nodules, pseudo-abscesses, facial edema Inflammatory nodules, giant pseudoabscesses Inflammatory nodules, facial angioedema Inflammatory nodules, pseudo-abscesses Inflammatory nodules Inflammatory nodules Inflammatory nodules, pseudo-abscesses Inflammatory nodules Mild inflammatory nodules

Treatmentà Antibioticsz/Allopurinol betamethasonez/HCQ Antibioticsz/prednisone HCQ Antibioticsz/prednisone HCQ Antibioticsz/betamethasone prednisone Antibioticsz/prednisone HCQ Prednisone Prednisone Antibioticsz/prednisone Antibioticsz/prednisone NSAIDs only

Follow-Up/Timey Residual nodules/24 Lost to follow-up In remission/48 In remission/18 Remission/lost 6 In remission/15 Mild bouts/41 Recurrent bouts/15 Lost/14 In remission/6

ÃNonsteroidal anti-inflammatory drugs (NSAIDs) were given in all cases.

Total follow-up until November 2007 (in months). Local injection of betamethasone (3 mg/mL). z Amoxicillin-clavulanic acid 875/125 mg three times a day for 4 weeks; ciprofloxacin 500 mg twice a day for 4 weeks. HCQ = hydroxychloroquine (6 mg/kg per day).

1,800 to 2,400 mg/d and intralesional steroids (betamethasone). Each vial contained 3 mg of betamethasone phosphate and 3 mg of betamethasone acetate in a total volume of 2 mL. According to the size and inflammatory aspect of the nodules, we injected betamethasone, 0.1 to 0.5 cm3 per nodule, usually with no dilution. Oral prednisone (0.2– 0.4 mg/kg per day) was administered in eight cases (80%), hydroxychloroquine (6 mg/kg per day) in four cases (40%), and allopurinol (up to 400 mg/d) in one case (10%) (Table 3). One patient was treated with NSAIDs only (case 10).

nal steroids and small doses of oral prednisone. Case 8 was treated with ciprofloxacin 500 mg twice a day for 4 weeks. No response was obtained. Previously, she had been placed on amoxicillin–clavulanic acid 875/125 mg three times a day for 3 weeks, with no clinical response. No systemic complaints have appeared in any patients in this series. High serum ACE levels persisted in cases 1 and 3, although they were asymptomatic. No granulomatous disorders or other systemic immune-mediated diseases appeared in this subgroup of patients with high ACE levels.

Follow-Up Follow-up of the 10 patients can be seen in Table 3. Average clinical follow-up was 20.1 months (range 6–48). In brief, at the time of writing this article, five patients (Cases 1, 3, 4, 6, and 10) were in remission. Patient 5 was in remission but was lost to follow-up at 6 months. Patients 2 and 9 were lost to follow-up. Cases 7 and 8 had recurrent inflammatory bouts. Case 7 was not placed on antibiotic treatment. Her inflammatory flares were controlled with intralesioDiscussion Delayed granulomatous reactions have been related to collagen, silicone, polylactic acid, polyalkylimide, hyaluronic acid, Gore-Tex, and methacrylate implants.1,5,15–17 The same types of adverse reactions have been described with the use of combinations of methacrylate–collagen and ethyl–methacrylate– hyaluronic acid.16,18 Some different delayed adverse reactions to PA have also been reported, mainly

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skin induration, inflammatory nodules, and pseudoabscesses.1,7–11,13–16,19 Since becoming available, PA is an increasingly commonly used filler in Europe. PA is a homogeneous gel consisting of a backbone of 97.5% sterile, pyrogen-free water and 2.5% cross-linked PA, which is nonresorbable.8,16 It is distributed in a prefilled syringe (Contura Inc., Soeborg, Denmark). The product has been thoroughly tested and cleared for toxicity and antigenicity,9–11 but adverse events occur,1,7–11,13–16,19 as they do with all types of fillers. Nevertheless, in a prospective multicenter study of 101 patients monitored over 24 months, von Buelow found only two cases of late, adverse effects related to PA.12 In an extensive, prospective study of case reports volunteered by injecting physicians over a 28-month period, Christensen and colleagues16 reported 55 adverse effects out of 40,000 people injected. Only eight cases (8/55) had a delay of more than 31 days (range 2–364 days; median 12 days). In two of these cases, the filler was badly positioned, and in another two, the only adverse effect was herpes labialis. Thus, only four patients in the Christensen series had true intermediate or delayed granulomas related to PA. Our series showed 10 cases of extensive facial inflammatory nodulesF granulomasFin patients injected only with PA. In this series, all patients who agreed to blood analysis had high levels of acute-phase reactants (CRP and fibrinogen), so underlying inflammatory processes in different stages had to be present. High LDH levels (1/4; 25%) can also indicate different conditions, for instance, liver disease, hemolytic anemia, or lymphoproliferative diseases. They may also be related to lymphocyte or macrophage activation, which is the most probable explanation in our cases. Likewise, high ACE levels (3/4; 75%) may be secondary to macrophage and granulomatous immune responses. Similar results were reported for other granulomatous immune-mediated diseases such as sarcoidosis and sarcoidosis-related disorders20 and sarcoidosis related to implant fillers.21,22 Plasma ACE values remained high in two patients (cases 1 and 3), although they remain asymptomatic. All bioimplants can, in vitro, elicit a primary immunemediated foreign-body-type reaction based on mac-

rophage activation and the induction of T-cell response.10,17,18,23–25 In theory, gradual development of network collagen fibers around the particles appears to coincide with a decrease in the inflammatory reaction, but so-called stable granulomas26 may evolve into a progressive abnormal granulomatous response to fillers. Sometimes, undesirable effects appear during minor trauma or after infection.1,8,17 In some cases in our series, certain bouts were related to facial trauma or infectious processes. This clinical correlation highlights the possible role of infectious agents as a triggering factor for the development of pathologic immune-mediated reactions.8,16,17 In theory, two or more different antigenic stimuli may increase the risk of abnormal immune response and produce immune-mediated adverse effects.27 In this series, one patient (case 2) had probably previously filled with HA. Although no adverse effects were recorded in relation to these previous fillers, they may have contributed to the current clinical problems. In addition to local steroid treatment, we used antibiotics, NSAIDs, and prednisone (Table 3). Antimalarials (hydroxychloroquine) were used in the same way as in other granulomatous or immunemediated diseases.20 Antimalarials also have many anti-inflammatory, anti-aggregant, and immuneregulatory properties.28,29 Cases of granulomatous reactions secondary to implant fillers have been treated with hydroxychloroquine.17,29,30 Allopurinol was administered to one patient (case 1). Allopurinol has also been used as a treatment for cutaneous sarcoidosis and granuloma related to implant fillers.31,32 Although in our series there was evidence of bacterial infection in only one case, as suggested by Christensen,8,16 antibiotics were used in seven patients (70%) but with no improvement; therefore, the relevance of antibiotic treatment is questioned. In the Christensen report,16 only 10 cases (10/55) were cured with antibiotics alone or in combination with other drugs. The treatment of similar clinical conditions associated with other implant fillers, PA included, has produced conflicting results regarding antibiotic treatment.1,15,17,30 As commented earlier, some cases of adverse effects related to fillers have

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been related to infections, such as bronchitis, pharyngitis, influenza, or pneumonia, suggesting that bacteria or viruses may play some role.8,16 Thus, the exact value of the bacterial presence as a primary causative factor of idiopathic granulomatous, immune-mediated disorders or related to bioimplants is not truly known.33 We think that this type of delayed complication related to implant fillers, according to histopathologic data and considering the few cases of bacteria recovered in the samples, may be due to a delayed type of hypersensitivity (type 4) reaction.34 In this series and in previous experiences, antibiotic treatment showed no effectiveness.17,29 The disparity between our results and those of Christensen and colleagues16 may be due to, among other factors, the time when antibiotics were administered. Christensen reported better results if antibiotics were begun immediately after granulomas appear. In cases in which antibiotics seem to be useful, it is unclear whether this is because of bactericidal properties, or their anti-inflammatory or immunemodulating effects.35,36 In this series of patients, the long-term follow-up showed better outcomes than those obtained in similar series of patients with delayed-onset side effects related to other bioimplants.17,19 We had 5 cases with sustained remission, and another case was lost to follow-up in clinical remission. Two cases persist with recurrent inflammatory nodules, is spite of the treatment used. According to our own experience in severe, recurrent cases related to other fillers, other drugs, such as calcineurin inhibitors, should be offered to these patients if recurrence occurs (Alijotas-Reig J, unpublished data). What is the prevalence of the delayed immunemediated adverse effects related to PA compounds? Based on current information, it is difficult to answer this question. On the one hand, we do not know the real number of cases that have developed delayed adverse effects, because of the tendency of many doctors not to report negative events. On the other hand, we do not have information about the total number of cases treated with PA and the volume or number of times that PA was injected into

each patient. However, we do know that almost 16,000 mL was sold in Spain from January 2001 to June 2005 (Real Lasting Group, the dealer of Aquamid in Spain). Although infrequent, perhaps in predisposed hosts, PA injections may cause delayed, moderate to severe immune-mediated adverse effects. Considering the increased use of PA in Europe and probably in the future in the United States, doctors should be aware that intermediate or delayed adverse effects can occur with PA dermal injections.

Acknowledgments The authors would like to acknowledge all members of the Sociedad Espanola de ˜ Medicina y Cirugıa Cosmetica for sending us the ´ ´ medical records and all of the patients who permitted us to perform this study. We also give thanks to Mrs. Maureen Shaughnessy (USA), who holds a Masters in Technical Translation, Rovira i Virgili University, Tarragona, Spain, for her help in revising the English style and grammar of the manuscript. This study was partially supported by a grant from the Sociedad Espanola de Medicina y Cirugıa ˜ ´ Cosmetica. ´

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Address correspondence and reprint requests to: Jaume Alijotas-Reig, MD, PhD, Josep Ma de Segarra, 2-F, 08190-Sant Cugat del Valles, Barcelona, Spain, or ´ e-mail: 16297jar@comb.es, e-mail: jalijotas@vhebron.net

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