Cosmetic Permanent Fillers es for Soft Tissue Augmentation A New Contraindication for Interferon Therapies Joerg Fischer, MD; Gisela Metzler, MD; Martin Schaller, PRD Background: Most of the new fillers used for soft ts- sue augmentation in aesthetic dermatology are consid- ered well tolerated, but very little data are available on their long-term tolerability, especially in patients rec ing immunomodulatory therapy Observations: A 48-year-old woman presented with disfiguring facial edema 10 weeks after she began anti- viral therapy with peginterferon alfa-2a and ribavirin for chronic hepatitis C infection. The major affected sites had been treated 10 years before with Artecoll, « permanent filler containing polymethylmethacrylate. A lyeatment allempt with allopurinol was initiated while antiviral therapy was continued and was successfully completed after 6 months. Despite significant improve- ment, extended plast surgery was necessary for facial Conelusions: The normal host response to « cosmetic filler is a weak granulomatous reaction, Interferon and other imimunostimulatory medications can lead to an ex- acerbation of this preext ‘mation that is quite similar to interferon-triggered sar- coidosis. This potential long-term risk has medicolegal ling low-grade chronic inflam- {implications for informed consent and for the potential use of both permanent fillers and interferon, Arch Dermatol, 2007:143:507-510 Author Affiliations: Department of Dermatology Eberhard-Karls- University Tubingen, Tubingen, Germany. Downloaded From: https: OFT TISSUE AUGMENTATION Is 4 common procedure, for which a wide variety of eos metic fillers are used. The tar ‘group for these interven- ‘oF rejuvenation purposes is mainly composed of middle-aged women, The main aims are to smooth wrinkles or creases in perioral, periocu- lar,and cheek areas and to produce an ar- Ulicial augmentation of lip oF eheek vol- lume, These procedures are sometimes performed in individuals who might need immunomodulatory therapy years later for a life-threatening disease such as chronic hepatitis C infection oF malignant mela- noma. Most of the new fillers are constd- cred well tolerated, Injectable aesthetic mi- croimplants such as Bioplastique, Artecol, and Dermalive are highly regarded be- cause they are inert like silicone, tend not to migrate in the tissue because of the in duction of human collagen production, and usually do not induce much of host immune response. A certain degree of low- grade inflammation duc tothe use of cos- metic fillers is unavoidable; this inflam- mation is the likely link for interactions between cosmetic fillers and interferon, To our knowledge, the interaction of cos- ‘metic fillers and interferons has not been described in the medical literature oF ‘manufacturer databases, but we recently encountered such a problem, —_ Enea] A 48-year old woman received subeuta- neous injections of peginterferon alfa-2a (60 pw/vk) and oral ribavirin therapy (400 mg/d) for chronic hepatitis C infection. Ten weeks after the initiation of therapy she presented witha 2-week history of pro- agressive disfiguring facial edema. She had blue-red swelling mainly involving the up- perand lower lips, nasolabial grooves, and flabella (Figure 1). Ten year earlier, these sites had heen treated with the polymeth- ylmethacrylate (PMMA)-containing cos- ‘metic permanent filler Artecoll (Artes Medical Inc, San Diego, Calif) to smooth wrinkles and to augment the lips. There was no history of sarcoidosis or tuberct- losis. A subcutaneous papule was pal- pable in an appendectomy sear on phys cal examination, but no changes were detectable in the scars from breast aug- ‘mentation surgery. An x-ray film of the (©2007 American Medical Association. AI rights reserved, jamanetwork.comy/ on O1/11/2021Figure 1. Sueling of the ps and formation of est long thet nasal yoore al presotation (A), ater 15 weoks (8) ard 9 days af the ith lst suey (0 chest showed no sign of hilar lymphadenopathy. The an- siotensin-converting enzyme level was elevated at 43 U/L, (reference range, 8-21 U/L). Antiviral therapy was con- nud at the same dosage. Oral allopurinol therapy was Initiated at a maximum dose of 600 mg/d, because of a previous report deseribing its efficacy in the treatment of PMMA granulomas." Six weeks later, the facial swell- ing was slowly decreasing, but no significant fading of the discoloration had occurred. Ten weeks after the pa- -t’s initial visit to our dermatology department, cys Jc nodules appeared along nasolabial grooves, and at 15 weeks there was an expanding ulcer in the glabellar re- gion, Antiviral therapy was completed as scheduled al- {er 6 months, No virus load was observed at the end of antiviral therapy or during follow-up. Noticeable im- provement of facial edema accentuated the discolors- lion of the injected sites as well as the nodules along na- solabial grooves, Ultrasonographic examination of the nodule on the left side of the face demonstrated a sep- late cyst measuring 55 X 117.5 mm in diameter with dorsal sonic enhancement, For diagnostic and therapeu lic purposes, the lesion was excised. Histologic exami nation revealed a dense sarcoidal granulomatous infil trate at the dermal-subcutancous fat border surrounding densely packed, small, round cystic spaces that con- lained translucent, nonbirefringent, uniformly sized mi- crospheres (Figure 2). On electron microscopy, some of the microspheres had lost their smooth surface, while others had leaked into the surrounding tissue. The sub- cutaneous papule in the appendectomy scar was ex- ised at the same time and showed sarcoidal granuloma- tous dermal infiltrates with giant cells engulfing birefringent foreign material, most likely suture rem- nants. During the next 16 weeks of allopurinol therapy the discoloration atthe injection sites improved, the nod- ules along the nasolabial grooves partially resolved, and the glabellar uleer healed spontaneously. Allopurinol therapy was discontinued after 8 months. Except for an insignificant increase in liver enzyme levels and a slight hhair loss, the therapy was well tolerated. The decrease {in uric acid levels showed that the patient had been com- pliant for the entire period. Despite this impressive im- provement, 5 surgeries were required for facial recon- struction over the next 8 months. The last follow-up visit occurred 17 months after the first contact. An x-ray film of the chest still showed no sign of hilar Iymphadenop- athy. The angiotensin-converting enzyme level had de- creased but was still slightly elevated at 30 U/L. There was no relapse of hepatitis C. Se Artecoll isa injectable permanent cosmetic filler with a biphasic structure: fine 32- to 40-pm-diameter PMMA, microspheres (solid phase) are suspended in a solution containing 3.5% bovine collagen solution and 0.3% docaine hydrochloride (liquid phase). The filler has to, be placed at the dermal-subcutaneous fat border by means of a pretunneling injection technique. After the implant is placed, the collagen carrier is phagocytized by macro- phages over 3 months and replaced by human fibro- blasts and collagen fibers, which fix the PMMA micro- spheres. The permanent cosmetic fillers that are mainly being used at present (eg, Artecoll, Bioplastique, Der- alive, Dermadeep, Dow Corning, and Silskin) are gen- erally considered to be well tolerated. Filler-induced granulomas are a rare adverse effect and cannot always be clearly distinguished from “nodules” that are caused by uneven tissue distribution of the product, Mos fille induced granulomas, such as asymptomatic dermal pap- ules oF nodules," are excised because of unsatisfactory cosmetic results, Histologic examination of these cases showed that the type of granuloma depends on the type of cosmetic filler that is used. Fillers that contain PMMA, microspheres (eg, Artecoll) or acrylic hydrogel particles (eg, Dermalive) can cause foreign body-type granulo- (©2007 American Medical Association. AI rights reserved, jamanetwork.comy/ on O1/11/2021Figure 2. Hscloge examin issue (Band [are ‘mas that are consistent with sarcoidal granulomas." Fill: ers containing silicone (eg, loplastique) can induce eys- Uicand macrophagi-type granllomas."* More severe cases with blue-red discoloration or large areas of involve- rncnt are rare and tend to appear years alter the injec- Uions.!2* The cases that have been reported have in- volved Artecoll and Dermalive."*" To our knowledge, there have been no previous reports of persistent severe facial edema, Another unique aspect ofthe present case ts the gravity-dependent formation of eytic lesions a the inferior aspects ofthe nasolabial grooves, which argues against the assumption that PMMA microspheres do not migrate because they induce anchoring human colla- gen. High-grade inflammation scems to mobilize the mi- crospheres by inducing collagenases. This observation has its histologic correlate in the densely packed nonbire- fringent microspheres without the expected inter- ‘wvined collagen fibers, Polymethylmethaceylate isan it~ ext material that is widely used in industry (Plexiglas) dentistry (Palavi), and medicine (Palacos) under dif cult mechanic and chemical conditions. The electron mi- croscopie findings of changes in the smooth surface of the microspheres and leakage inthe surrounding Usste raise the question about how inert this material rally is {nthe micromailiew of severe chronic inflammation. The interferon-triggered inflammatory response of fller-associated grantlomas isa new observation. Inter- on showed sarcial granulomatous inflates surrounding densl packed, smal rund cyst pars contain arlucent of pprxarata th same sin (on lacton microscopy sore ofthe microspheres sawed a changin hat smacth surace {eron-associated sarcoidosis sa rare but documented oc- currence.®* In larger series of patients with hepatitis € treated with interferon and ribavirin, new cases of sar- coidosis have occasionally appeared, with a prevalence of 0.2%. Mainly middle-aged women have been af- fected during the first 6 months of antiviral therapy. Cu- taneous and articular involvement were more frequent and hilar and extrapulmonary lymphadenopathy were less common in patients with interferon-triggered sar- coidosis than in those with non-interferon-triggered sarcoidosis. The prognosis of patients with interleron- Uriggered sarcoidosis is good. Improvement of sponts- neous remission is clearly related lo the discontinuation of antiviral therapy. Cutaneous manifestations may even resolve spontaneously during therapy. In one study. sys- temic steroids were required in 35% of individuals, and had a negative effect on the outcome of antiviral therapy. The observations on interferon-triggered sar- coidosis closely match our case. Elevated angiotensin- converting enzyme levels and sarcoidal granulomas around both suture material and cosmetic filler also sug- {gest cutaneous sarcoidosis in our case. Based on the ob- servations regarding sarcoidosis in patients with cos- ‘metic tattoos, the question as to whether the presence of polarizable foreign material within sarcoidal granulo- ‘mas is compatible with the diagnosis of sarcoidosis is cur renily being debated in the literature.’ The normal host (©2007 American Medical Association. AI rights reserved, Downloaded From: https:/jamanetwork.com/ on 01/11/2021response to cosmetic fillers isa granulomatous reaction. In our opinion, interferon can cause an exacerbation of preexisting low-grade chronic inflammation that should not be equated with cutaneous sarcoidosis. Nonetheless, the iinmunological mechanisms of Tyl re- sponse seem to be the same as in interferon-triggered sarcoidosis In our case, treatment with allopurinol at a maximum dose of 600 mg/dl was well tolerated and did not interfere with the outcome of antiviral therapy. Allopurinol is thought to modulate inflammation as a fre radical scav- enger. It appears to produce a definite but slow and par- tial improvement, although completely separating its ben- efits from spontaneous improvement, especially alter antiviral therapy is discontinued, is not possible. This report demonstrates the potential long-term risks and touches on the medicolegal implications of cos- metic intervention with injectable aesthetic microim- plants. The risk of severe interaction with interferon oF other immunostimulatory medications should be in- cluded in the consent form for injectable aesthetic mi- croimplants, Becatise patients often fal to mention cos- metic procedures, physicians should ask about possible history of permanent soft tissue augmentation before pre- scribing interferon, and then in cases in which a perma- nent filler is present, they should review the indications for interferon and other immunostimulatory medica- dons very carelully. Accepted for Publication: October 31, 2006. Correspondence: Martin Schaller, MD, PhD, Depart- ment of Dermatology, Eberhard-Karls-University Tuebingen, Licbermeisterstr. 25, 72076 Tuebingen, Germany (martin schaller@med uni-tuebingen.de). Author Contributions: Study concept and design: Fischer and Schaller. Acquisition of data: Fischer and Sehaller. Analysis and interpretation of data: Fischer, Metzler, and Schaller. Drafting of the manuscript: Fischer. Critical re- Vision ofthe manuscript for important intellectual content: Fischer, Metzler, and Schaller. Administrative, technical, and material support: Schaller. Study supervision: Schaller, Financial Disclosure: None reported, Acknowledgment: We thank Hannelore Bischof, Birgit Pehrenbacher, Helga Moller, and Renate Nordin, Univer- sity of Tubingen, Germany, for excellent technical assis- tance and Walter Burgdorf, MD, University of Munich, Munich, Germany, for critical review of the manuscript. —_ Ess} 1. iro 2M Lanter Mt , Strode. tt Fee bey gran Tomas xe aymaynehaeate microphase ih lopariol Ach Dermat! 208 8017-20. udp, Saver, Soule Petrov et, Farsignbody galas ue ‘oijeeuble aesthetemireimplas. J Sy Pte 19828 13-17 Lamba, Seneon Pate seen Kale , Orta ranma arin cosmete ilersistpalgi and ei study 11 ese. ‘Or Pt ed 20043818120. agua ldo ML, Nr Mt Abra actions to intl ae Phe mierimpans An Jerre 200728187202 ames sna) ard ea Sado in pate wih chronic aps tes Crus icon aaj 68 cases. Maden 205 369-0 HustEA Mau Suciess assocated wth pgylasclarran aaa be insane apt Cae parade oh era. ‘rh Dermal 200614 86568, ‘ntanoveh 0, Clan PDeelopmnt of sarc incosmee tues. Ach ‘Dermat 2005 141960472 (©2007 American Medical Association. AI rights reserved, jamanetwork.comy/ on O1/11/2021