The correction of cutaneous atrophy sequelae and cosmetic treatments in patients with Connective tissue disorders (CTD), such as scleroderma and lupus erythematosus, is Controversial since there is a theoretical risk of re-triggering the disease by immune activation [1].

Several types of treatments have been tried, with a varying degree of success. Surgical procedures including skin flaps and grafts, autologous fat graft and injectable soft tissue fillers, such as hyaluronic acid (HA), calcium hydroxylapatite (CaHA), poly-l-lactic acid (PLLA), polycaprolactone (PCL) and others have been reported in literature [2-8].

Despite the concern of autoimmune disease reactivation by these kind of procedures, recent studies have demonstrated that dermal fillers seem to be safe as treatment of cutaneous defects in this patient population [1, 3,4,8].

Among the different types of fillers available, the choice should be based on collagen stimulating properties, safety, cost and durability. 7,9,16 In addition, for patients with CTD, the filler is expected to generate a minimal inflammatory response, to reduce the risk of antibody formation and disease activation [1,3,4].

Radiesse® (Merz Pharmaceuticals GmbH, Frankfurt, Germany) is a biocompatible biostimulatory CaHA soft tissue filler frequently used in aesthetic medicine whose security profile is well established. It is composed of 30% CaHA microspheres of 25-45µm diameter in 70% of sodium carboxymethylcellulose gel. The CaHa microspheres are identical in composition to the mineral substance of human bones and teeth [9-16].

Several in vivo studies involving humans have shown that small-sized CaHA microspheres, as used in Radiesse®, stimulate fibroblasts neocollagenesis without fibroblast hyperplasia and with minimal inflammatory response [16-23].

Considering the availability of a biocompatible and effective dermal filler and its sensible use in reconstructive and aesthetic medicine, this study aims to report a case of good response after a CaHA filler treatment to improve skin quality in a patient with stable scleroderma.

A 72-year-old woman presented in a dermatological clinic in 2020 due to sagging and aging skin. She was diagnosed with scleroderma in 2013 and she made use at the time of Prednisone and methotrexate, with disease control.

Prior cosmetic procedure in 2015 was performed with a PLLA filler for facial wrinkles and skin aging. However, she presented a serious reactivation of scleroderma following the filler application. Symptoms like facial edema, visual clouding, tinnitus, dysphagia and myositis persisted for almost 6 months and she had all her medications doses augmented until new disease control was achieved.

Upon presentation, her disease was stable for 5 years and she was in use of 2.5mg of prednisone and 500mg of mycophenolate mofetil twice a day. She denied any symptoms at the time and, on medical examination, it was observed loss of facial contour, sagging and thinning of the skin. After informed consent was obtained, three separate sessions of CaHA injections were performed, with 3 months and one-year intervals between them.

Radiesse Duo ® (Merz Pharmaceuticals GmbH, Frankfurt, Germany) comes in a 1.5 mL syringe and a correction factor of 1:1 was used, with saline solution and 2% lidocaine as diluent. A 25-gauge cannula was positioned in the subdermal plane and 0,1ml aliquots were distributed in a fan technique. In the first session, the regions of the zygomatic cheeks, malar cheek and sub malar were prioritized. In the second, more product was distributed lateral

to the ligament line, in order to obtain more lifting effect. In the third session, focus was given to the mandibular line and chin, avoiding the jaw region.

Figure 1: Material utilized and application of the filler in the sub dermal plane.

The result was immediate due to volumizing effect of the carboxymethylcellulose gel. As it is absorbed, it is progressively replaced by new collagen fibers. Skin quality improvement and better facial contour was clearly seen by the second month after each application and maximum visible effect by 6th month. She reported minimal swelling one day after procedures, but no other adverse effects.

Figure 2: A, B and C: April 2021 (First session); D, E and F: July 2022 (12 months after 2^nd session - Third session); G, H and I: October 2022 (3 months after 3rd session).

Figure 3: Closer view of pictures E and H. Three months after one CaHA session. Jaw reduction and better facial contour are observed.

Figure 4: Vector comparison between January 2022 and October 2022.

The term scleroderma is used to describe a connective tissue disorder that comprises a wide spectrum of manifestations that may be limited to the skin or involve multiple organs, with different severities and repercussions [24].

The etiology is still incompletely understood, but it is believed to have an autoimmune pathogenesis triggered by viral infection or certain environmental toxins and drugs in genetically susceptible hosts. The innate and adaptive immune activation and vascular damage are followed by excessive collagen synthesis by fibroblasts [24].

Corresponding to the autoimmune etiology, initial treatment is based on immunosuppressants. After the patient’s condition is stabilized, it is possible to address the remaining damage and symptoms caused by organ involvement and skin atrophy [2,3,5,24].

Surgical approaches like skin flaps and grafts or autologous fat graft have several disadvantages that include donor site scars, unnatural appearance at the recipient site, high cost, prolonged surgical times, requirement of skilled practitioners to perform the procedure and a facility to store the extracted fat [2,5].

Injectable soft tissue fillers, such as hyaluronic acid (HA), calcium hydroxylapatite (CaHA), poly-l-lactic acid (PLLA) present themselves as less invasive, less expensive and, even though, effective alternatives for cosmetic correction of the asymmetries [2,5,6,7].

The literature about the use of soft tissue fillers in CTD is still scarce. However, recent studies have demonstrated that dermal fillers seem to be safe in this patient population [1,3,4,8]. Furthermore, our group recently published a case report of a patient with ParryRomberg Syndrome successfully treated with CaHA filler [25].

Radiesse® is a biocompatible injectable filler composed of 25-45µm microspheres of CaHa, identical in composition to the mineral component of human bone and teeth, suspended in a carboxymethylcellulose gel. It was approved by the American Food and Drug Administration (FDA) for the correction of moderate-to-severe wrinkles and folds in the face, and/or as a corrective measure in the treatment of facial fat loss in individuals infected with HIV. In Europe, CaHa is CE-marked for tissue augmentation, including treatment of nasolabial folds, marionette lines, prejowl sulcus and jaw recontouring [13-16].Following implantation, the carrier gel is reabsorbed and gradually replaced by fibrovascular stroma, mainly formed by new collagen type III fibers, generating a long lasting volumization and improvement in skin quality. With time, collagen type III is gradually replaced by collagen type I. Recent studies have shown that CaHA also induces proteoglycans and elastin formation [12,17-20,22].

One study with cultured cells have suggested that CaHA microspheres with different sizes and shapes may generate different fibroblast responses, that is, microspheres of 300µm induced fibroblast proliferation, while small-sized microspheres of 40µm did not [26].

Moreover, microscopy and ultrastructural studies demonstrate that all the CaHA collagen stimulation process occurs with minimal immunological reaction with a slow modification of the filler by the action of the connective tissue cells. On the other hand, studies have shown that PLLA and PCL might induce their collagen stimuli effects based on inflammatory reaction, which could explain this rare case of disease activation when our patient was exposed to PLLA [16,23,30,31].

CaHA security has been proven by several studies. A review of 21 articles including 2779 patients treated with CaHA showed a low incidence of adverse effects. Nodule formation was the most common (3%), followed by persistent inflammation/ swelling (2%), persistent erythema (1%) and overcorrection (1%). 14 In contrast, the incidence of nodule formation after use of PLLA filler is estimated to be around 13%. Different kinds of late complications have been related to HA fillers, such as hypersensitivity reactions, migrations, Tyndall effect, infections and abscess formation [9,10,13-16,27-31].

The estimated longevity of the effects of CaHA filler is 12 to 18 months. HA have shorter longevity, between 4 and 6 months. PLLA and PCL might have higher durability, up to 3 and 4 years, respectively, however further studies are needed to quantify and compare the level

of collagen produced by these fillers [11,20,32].

CaHA fillers are apparently possible alternatives for the correction of cutaneous atrophies and aesthetic treatments in patients with CTD, despite the theoretical risk of disease reactivation. Further studies are needed to compare more precisely the properties of the different fillers available on the market, regarding their mechanism of collagen induction, amount of collagen produced, durability and safeness in CTD population.

This report shows a successful case of cosmetic treatment in a patient with scleroderma using a CaHa filler, a product with good biocompatibility, efficacy and durability. Its use as semi-permanent filler for facial contouring and rejuvenation seems to be also applicable for patients with stable CTD and it is a minimally invasive procedure that can replace other expensive and complex techniques.

Funding Information

All costs involved in the reported treatment were funded by the patient's own means. There was no financial contribution for this study to be carried out, neither for the authors nor for the patient.

Ethical Approval

This study (case report) was conducted in accordance with regional laws (Brazil) and good clinical practice. It was approved by the ethics committee of the institution: "OBRAS SOCIAIS E EDUCACIONAIS DE LUZ" conclusion number 5.880.664. The patient provided written informed consent for the use of both their data and associated images prior to the treatment.

Conflict Of Interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and publication of this article.

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