Diseases produced by infiltration of filler or modeling substances for esthetic purposes are called Iatrogenic Allogenosis. ‘Iatrogenic’ means induced by physicians or otherwise trained persons, and ‘Allogenosis’ means produced by a foreign substance (eg aspirin) [1] [2]. It is important to highlight that this is not only a disease where there is a granulomatous response to a foreign body, but also it can also originate locally and with systemic manifestations. Symptoms can be registered even 20 years after inoculation [3] [4] [5].

Filler substances injected with esthetic purposes originated in the XVII century, but their original purpose was therapeutic [3] [6] [7]. In 1899, Gersunyhas described paraffin prosthesis in patients having orchidectomies, a consequence of testicular tuberculosis. Their use was also described in patients with cleft lip and cleft palate [7] [8] [9]. The first histopathological descriptions were done in 1906 under the name of ‘paraffinoma’ [10]. The first applications of paraffin and liquid silicone were done during the 50s. Liquid silicone, a mixture of substances such as dimethylpolysiloxane and fatty acids like mineral oil or olive oil were used in Japan, e.g. Sakurai's formula consisting of 1% olive oil industry combined with impure silicon applied in various sites of the body such as breasts and pelvic limbs [5].

At the beginning of 1960s, the use of liquid silicone became popular in the United States (Las Vegas, Nevada). Approximately 20,000 to 40,000 individuals were injected under these circumstances, and the injected areas included breasts, faces, legs, and buttocks. Large volumes (750 to 2000 cc) were injected. Granulomatous inflammatory reaction subsequent to the injection was called siliconoma. After that experience, Norman Orentreich developed the microdroplet technique. This technique was developed to obtain a more gradual correction and minimize the complications that had been seen with large-volume injections [11] [12] [13].

During the 70s and 80s, Graft vs Host Disease (GvH-disease) was described as a type of autoimmune disease produced by this type of prosthesis. The main symptoms described were Raynaud’s phenomenon, Sclerodactyly and pulmonary fibrosis, similar to systemic sclerosis symptoms [14] [15]. GvH-disease was first described in patients undergoing bone marrow transplantation; the difference with siliconoma is that lymphoid tissue must be present. Now, this kind of manifestations are not expected due to the characteristics of the new breast prosthesis. These prostheses have 6 or 7 layers of elastomer in order to avoid rupture and infiltration of materials [16] [17] [18].

Iatrogenic allogenosis produces a granulomatous immunological response. These granulomas show increased slL-1 TN-α cytokine levels around the infiltration areas, as well as in serum, and are composed of a core of epithelial cells with lymphocytes, plasma cells and dendritic cells. On the other hand, foreign body granulomas contain macrophages, giant cells and fibroblasts, with no presence of lymphocytes [19] [20] [21] [22]. Pathophysiologically, fibrinogen is unfolded when in contact with the biopolymer substances, exposing two hidden epitopes, P1 (13) and P2 (377-395). This fibrinogen denaturation induces an immunologic response with antibody formation [18] [23] [24].

During the last few years, immunologists have described a disease characterized by systemic and autoimmune manifestations called Autoimmune/Inflammatory Syndrome induced by Adjuvants (ASIA). In this syndrome, the substance can also be a vaccine whereas in Iatrogenic Allogenosis the biopolymers or filler substances or other substances injected with esthetic purposes are the cause of induction of the disease [9].

The aim of this study was to describe the most relevant clinical parameters in a series of cases where patients were infiltrated with modeling (filler) substances for esthetics purposes. These patients were treated by a multidisciplinary team at two main reference hospitals in Caracas, Venezuela. The team also received support from a plastic surgeon with expertise in breast prostheses and biopolymer diseases.

A treatment flowchart was designed for a better control of patients undergoing filler substances infiltration with esthetic purposes who developed local or systemic manifestations.

Patients with local and systemic manifestations after infiltration with biopolymers or other filler substances for esthetic purposes were included in study carried out between March 2009 and October 2011. The patients attended the Dermatology, Plastic Surgery and Rheumatology outpatient clinics at the Hospital Universitario de Caracas, Hospital Vargas de Caracas and Clínica El Avila (Caracas). The first two are public hospitals and the other one is a private clinic.

Patients received a self-evaluation survey format for registering demographic data, type of substance infiltrated, amount of substance infiltrated, personal and family history of autoimmune diseases, infiltration site, onset of symptoms, description of signs and symptoms, and pharmacological or physical therapy (e.g. local heat application or ultrasound) treatments received before inclusion into the study.

The method chosen for measuring silicon blood levels was ICP / AES (Inductively coupled plasma atomic emission spectroscopy), with reference levels <0.3 mg / dl (Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA). TNF-a serum levels were measured by an ELISA method, with reference levels 1.2-15.3 pg / ml (Quest Diagnostics Nichols Institute). IL-1B levels were measured by an ELISA method, with reference levels <3.9 pg / ml (Quest Diagnostics Nichols Institute). ANA and DNA were measured by immunofluorescence (Laboratorio InmunoXXI, Santa Paula. Caracas, Venezuela). Rheumatoid factor (RA Test) was measured by the nephelometric method (Laboratorio InmunoXXI. Santa Paula. Caracas, Venezuela). Anti ENAs (Anti Ro, Anti-La, Anti-SM and Anti-RNP) were measured by ELISA (Laboratorio InmunoXXI. Santa Paula. Caracas, Venezuela).

Initially, patients were treated with glucocorticoids. Subsequently, colchicine or hydroxychloroquine were added according to the lesion characteristics (size and localization) and the clinical manifestations (local or systemic). If the patient did not improve after three months (using clinical examination and imaging evaluation), an immunosuppressive treatment with azathioprine, colchicine, talidomide or mycophenolatemonofetil was added.

The treatment protocol was based on a single flow chart. Treatment began with moderate doses of low potency steroids (deflazacort); colchicine or antimalarials were intiated during a follow-up visit 45 days later. Control visits were done every three months in order to measure a possible favorable response to or failure of medication. In case of failure, the dose was increased or changed to cytostatic drugs; this evaluation was done according to three parameters:

• • Clinical evaluation (table 1)
• • Laboratory: Acute phase reactants persistently elevated: Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP)
• • Imaging (MRI or Ultrasonography).

Severity was defined according to the most serious complications suffered by patients after biopolymer infiltration: functional disability of the affected limb, development of autoimmune disease (according to ACR criteria), sepsis and necrosis (table 1).

Magnetic Resonance Imaging (MRI) was used in all patients with suspected filler (biopolymer) disease in order to define the amount of inoculated material, location, severity and disease activity. This activity was defined according to what is observed in a hyperintensivity granuloma T2 image.

We have used two ultrasound equipments. One was used to assess the degree of involvement of biopolymers such as size, amount, location, inflammation and migration. The second ultrasound was used only for specifications of therapeutic use, and it was done in all patients with localized and well-defined lesions.

Therapeutic ultrasonography was done with an ultrasound Chattanooga 2782K Intelect® Mobile 2.5 watts/cms2. The type of heat generated is deep in order to ameliorate inflammation and fibrosis. The frequency of therapy was once daily for a total of 10 sessions followed by 10 additional interdaily sessions. Sessions lasted 5 minutes in small areas (<7.5cm) and 10 minutes in larger areas (> 7.5 cm).

All cases were routinely submitted to the following laboratory tests: blood chemistry and complete blood count tests, antinuclear antibodies (ANA), DNA double stranded antibodies (Anti-dsDNA), single stranded DNA (ssDNA), anticytoplasmic antibodies (antibodies to Extractable Nuclear Antigens-ENA), Rheumatoid Factor, anti-cyclic citrullinated peptide antibodies (Anti-CCP), serum silicon levels and TNF-α serum levels. Other examinations included: chest X-ray, ultrasonography and MRI of the lesion, which were performed at three different time points, before treatment, 3 months after, and finally, 6 months after the treatment. Sequential pictures of the lesion were taken, and in those cases where it was possible to obtain a fluid sample, a histological examination and culture of the lesion was also done.

Fibrosis: this term is used to refer to the formation of fibrous tissue as a reaction due to the accumulation of biopolymers in subcutaneous tissue.

Migration: this term is used to refer to gravity displacement of biopolymers (non implants) used for esthetic purposes, such as polymethylmetecrylate (PMMA), due to the fact that they are non-absorbable synthetic particles. When the patients receive a large amount of this material (volumes>500cc) there is a risk of migration of material due to gravity during sleeping positions, long distance walks, long periods of being standing, or even during relaxing massage sessions; on the other hand, some patients have antigravity migration, for which the mechanism is unknown. This material can migrate from the lower back region and from calves to ankles or plantar regions, causing inflammation in these tissues.

Patients were included using a quota methodology, during the time period between March 2009 to October 2011. Patients who presented local or systemic manifestations after inoculation of any kind of material for esthetic purposes were included. These patients were controlled at the Dermatology, Plastic Surgery or Rheumatology Departments belonging to the Hospital Universitario de Caracas, Hospital Vargas de Caracas or Clinica El Avila in Caracas, Venezuela (Table 2).

Most patients were female (96%) and 70% of them were housekeepers. Mean age was 36 years old. Forty-six percent of patients had a cigarette smoking background, 4% had an alcohol background, 2% had a drug abuse background and 56% presented a personal or family history of autoimmune disorder. Clinical manifestations were varied, being mainly cellulitis-like lesions and erythema and skin dischromia at the inoculation sites. The average occurrence time of clinic manifestations was 36 days, with a range between 1 to 435 days and in some isolated cases occurrence of manifestations was 11 years after inoculation of substances. Most patients were inoculated with unknown substances, or they referred that the esthetician informed them that the substance inoculated was liquid silicone.

Figure 1. Keloidscar.

One patient who was inoculated with a substance called Biofilm® (polimetilpolimetacrilato + dimetilpolisiloxano) showed large hyperchromic areas, very red, erythematous. The cosmetologist who treated her tried to compensate this error by applying long lasting (deposit) steroid injections such as triamcinolone (Kenacort®), producing more tissue depression at infiltration sites. Another patient showed a reaction three weeks after the infiltration of a substance called Biosiluet® (dimethylpolysiloxane) showing erythema, inflammation and a keloid scar at the infiltration site (Figure 1).

Figure 2. Breast with biopolymers (mastectomy and mammogram).

Another patient underwent a breast enlargement procedure with methacrylate infiltrations (750cc in each breast) showing erythema, deformity, and skin discoloration. The patient had to be submitted to a partial mastectomy due to pain (Figure 2).

We had one case in our private consultation of a patient who omitted information regarding biopolymer inoculations and underwent surgery for genital prolapse and vaginal rejuvenation. The biopolymers moved toward the lumbar nerve roots causing severe pain in L2-L3 dermatomes due to the position on the operating table during more than 45 minutes (obstetric position). This was treated with nerve root block and pain therapy.

Figure 3. Retractile scars

We have had 7% of patients with retractile scars and skin depressions (Figure 3) due to the use of high potency steroids (methylprednisolone), or who underwent revision surgery and removal using the Vasser® liposuction method, an ultrasound assisted liposuction that produces bone fat liquefaction, resulting in cellulitis-like skin lesions and skin dischromias.

Another patient presented pain 2 weeks after inoculation with mineral oil. A tissue extract culture reported Propionibacterium acnes infection (Figure 4).

Seventy five percent (75%) of patients improved after treatment with deflazacort + colchicine and/or hydroxychloroquine. Ninety two percent (92%) of these patients had a relapse after 5 months and were treated with azathioprine (Figure 5).

Figure 4. Aspiratingsecretion for culture.

Patients could develop local and systemic manifestations. The average onset of symptoms after esthetic procedures was 24 months (range from 1 month to 11 years). Patients injected with inert substances such as liquid silicone showed less severe clinical manifestations than patients injected with impure oily substances as motor oil, cooking oil, mineral oil. Nevertheless, in all these cases, treatment was successful using glucocorticoids and colchicine.

Infections: Less than 1% developed skin infections (at infiltration sites). Staphylococcus aureus followed by Propionibacterium acnes were isolated in secretion cultures. There was no evidence of atypical bacteria or mycobacterium infection.

Local Manifestations: Ninety percent of patients reported erythema, 58% skin pigmentation, 70% edema, 12% fibrosis, 25% keloids, 8% local infections, 2% fistulas, 5% skinnecrosis and 23% had displacement of implants due to gravity.

Figure 5. Iatrogenic Alogenosis: treatment scheme.

Systemic manifestations: Thirty eight percent of patients reported fever, 18% general pain, 17% arthralgia, 19% weight loss, 45% adynamia, 12% hair loss, 11% Raynaud's Syndrome and 12% livedo reticularis. Finally, 12% of patients developed a chronic autoimmune disease, of these, 3 patients (4%) developed psoriasis and were treated with anti-TNF. As a matter of curiosity, all psoriasis patients had first and/or second degree relatives with psoriasis.

Based on these results, the characteristics of our cases are different from those developed in a foreign body granuloma disease, mainly because we found autoantibodies and these patients developed systemic manifestations fulfilling the criteria of the American College of Rheumatology (ACR) for autoimmune diseases. Additionally, most of them had personal or family histories of an autoimmune disease.

We have noted a low percentage of post-inoculation infections (1%), not comparable with the high infection rates found in mesotherapy sessions. We observed that when the Vasser® liposuction method was used, patients had more intense symptoms than before the procedure, showing more severe dischromia and erythema. This is most likely due to the heat, which activates macrophages and reactive lymphocytes, triggering the inflammation cascade with migration of high number of macrophages and natural killer cells to the site.

In most cases, patients did not know which substance was injected and it was not possible to get a sample of the substance via puncture for histological study. In more severe cases anti-TNF therapy was used at doses used against granulomatous diseases (Crohn’s disease or Ulcerative rectocolitis), improving symptoms after about 3 months.

We have found that the main criteria for associating the occurrence of symptoms with a low response to treatment, were high levels of acute inflammation markers, low response to deflazacort, personal or family history of autoimmune disease, high serum levels of silicone and TNFα, and ANA (+) presence.

The content of the manuscript is original and it has not been published or accepted for publication, either in whole or in part, in any form. No part of the manuscript is currently under consideration for publication elsewhere.

Alberto Millan MD, Professor of Internal Medicine and Rheumatologistr from Universidad Central de Venezuela in Caracas, Venezuela, recommends this article for publication.

Ernesto Garcia MacGregor MD, Professor of Internal Medicine and Rheumatologist from La Universidad del Zulia (LUZ) in Maracaibo, Venezuela, recommends this article for publication.