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Long-term outcome of fat grafting to treat facial Systemic Sclerosis: a prospective cohort study

Long-term outcome of fat grafting to treat facial Systemic Sclerosis: a prospective cohort study Plastic and Reconstructive Surgery Advance Online Article DOI: 10.1097/PRS.0000000000012111 Long-term outcome of fat grafting to treat facial Systemic Sclerosis: a prospective cohort study 1,2,3* 1,2,3 Aurora Almadori MBBS, MSc, MSc, PhD; Michelle Griffin MBBS, MSc ; Jeon 1,2,3 4 Hyun MBBS, MSc; Esther Hansen BSC(HONS), DCLINPSY; Christopher P Denton 5 1,2,3 PhD, FRCP ; Peter EM Butler MD, FRCSI, FRCS, FRCS (Plast) . UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College London, London, United Kingdom Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom Charles Wolfson Centre for Reconstructive Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom Clinical Psychology, Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom Center for Rheumatology, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom *Corresponding author: Dr Aurora Almadori, MBBS, MSc. PhD Pond St, London NW3 2QG, United Kingom [email protected] [email protected] Financial Disclosure Statement: The authors have nothing to disclose. No funding was received for this study. Short Running Head: Long-Term Results of Facial Fat Grafting in Systemic Sclerosis ACCEPTED Plain language summary: Systemic sclerosis is characterized by subcutaneous tissue loss, skin fibrosis, restricted facial movement, and mouth opening. Fat grafting is a minimally invasive procedure that restores facial volume and ameliorates skin fibrosis. We conducted a study of 93 patients with SSc who were treated with fat grafting. After an average of 2.96 fat grafting procedures, the fat survival rate was 53.1% at the 3.11-year follow-up. In addition, significant improvements in oral function and patient quality of life were observed. Facial fat grafting is an efficient method to restore facial volume and improve oral function and quality of life in patients with scleroderma. Keywords: Systemic sclerosis; Scleroderma; Fibrosis; Fat grafting; Fat transfer; Lipofilling; Lipotransfer; Adipose-derived stem cells; Regenerative medicine; Fat survival. Data Access Statement: All relevant data are within the paper. Additional data supporting this publication are available upon request. Author Contributions: The work constitutes part of AA’s PhD at University College of London. AA, EA, CD and PEB contributed to the design and implementation of the research; AA collected the data; AA and JK analyzed the results; AA wrote of the manuscript; PEB and CD conceived the original and supervised the project and revised the manuscript; MG only supervised student JH. Manuscript word count: 2,999 words (excluding references). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited ACCEPTED Abstract word count: 190. ABSTRACT Background Systemic Sclerosis (SSc) is characterized by subcutaneous tissue loss and dermal fibrosis, with limited facial movement and mouth opening. Fat grafting is a minimally invasive technique used to restore facial volume and improve skin fibrosis. Materials and methods A cohort of 93 patients were assessed using 3D imaging (3dMD) before and after fat grafting. Secondary outcomes included physician-based assessment, mouth function (MHISS), psychological status, quality of life (DAS, HADS, VAS, BFNES), and patient- based satisfaction. Results After an average of 2.96 (±2.2) sessions of fat grafting, with an injection volume of 11.9 cc (±6) in each session, the overall retention rate was 53.1% (±0.17) at an average follow-up of 3.11 (±1.73) years. Patients undergoing 5+ interventions presented a higher retention rate (73.1% ±0.08%) than those receiving one or two treatments (45.2% ±0.09 and 50.5% ±0.15 respectively) (P<0.05). Significant improvements were found in mouth function (P<0.0001) and quality of life (P<0.0001). Conclusion Facial fat grafting is an effective technique for restoring facial volume and improving oral function and quality of life in patients with scleroderma. This study presents the largest number of patients published to date with the longest follow-up period. ACCEPTED BACKGROUND Systemic Sclerosis (SSc) is a chronic autoimmune disease characterized by abnormal deposition of extracellular matrix (ECM), with progressive fibrosis [1, 2]. It is classified into two subsets: limited cutaneous SSc (lcSSc) if the skin fibrosis is confined to the face and extremities; and diffuse cutaneous SSc (dcSSc) if the skin fibrosis extends on the trunk and proximal parts of the limbs [1, 2]. Skin fibrosis and subcutaneous tissue loss are hallmark manifestations that are particularly noticeable in the face. Thickened and hardened skin is responsible for a taut and mask-like appearance with diminished facial expression. Typical orofacial features include subcutaneous tissue loss, fibrotic skin firmly attached to the underlying planes, nasal alar resorption resulting in a pointed nose, perioral wrinkles, and mouth changes [2]. The lips are usually thinned (microcheilia), and the skin around the mouth is stretched with deep perioral radial wrinkles, loss of the vermilion border of the lips, and narrowing of the oral line with reduced motility and opening (microstomia) [2]. When salivary gland function is impaired, dryness of the oral mucosa can be a feature (xerostomia) [2, 3]. Life-threatening aspects of the disease (heart, lung, renal involvement) have been a therapeutic priority, but non-lethal manifestations, like facial and hand impairments, are becoming increasingly important [4], as patients with scleroderma presents impaired quality of life, poor mental health, self-image issues, depression, anxiety, and lower perception of general health compared to healthy controls [2, 4, 5, 6, 7]. Fat grafting is minimally invasive surgery largely used in plastic surgery not only to fill contour deformities but also to improve skin fibrosis and scarring [2, 8, 9, 10, 11]. Its use in scleroderma has been successful in correcting volumetric deformities in localized scleroderma [12, 13, 14, 15] and improving mouth or hand function in SSc [16, 17, 18, 19, 20, 21]. However, studies published thus far present a short follow-up period; therefore, data on the durability of the effect in facial scleroderma are currently lacking. Evidence of ACCEPTED the use of lipotransfer for other applications has shown that it is associated with unpredictable long-term results due to volume resorption, which is currently the main limitation of this technique [22, 23]. This prospective cohort study aimed to assess the long-term volumetric outcomes after fat grafting in patients with SSc. METHODS Trial design: This study included 93 patients who met our inclusion criteria: 1) previous diagnosis of SSc irrespectively of the disease subset (dcSSc and lcSSc); 2) age < 18–75 years; 3) stabilized SSc disease (at least 2 years); 4) stable lung and cardiac functionality; 5) noticeable orofacial modification; and 6) verified orofacial dysfunction assessed with the Mouth Handicap in Systemic Sclerosis Scale (MHISS). The following categories were considered ineligible: 1) pregnant women; 2) individuals suffering from a widespread infection or cancer; and 3) those unable to give written, informed consent in English. Patients were selected from the Rheumatology and Plastic Surgery outpatient clinics. They were offered repeated procedures based on their clinical signs and symptoms with 12 months interval between the procedures. Ethical approval: This prospective study was conducted after approval from the institutional and regional ethical committees in charge (REC Hampshire B ref 16/SC/0669; R&D ref 10006). ACCEPTED Surgical technique: Fat was harvested using 15 mm × 3 mm disposable cannulas with two holes of 1 mm diameter. Donor sites were abdomen or medial thighs, where usually a sufficient amount of fat is present irrespectively of the patients’ disease severity or Body Mass Index (BMI). Lipoaspirate was centrifuged at 3000 rpm for 3 min [8]. We used only the distal 3/4 of the lipoaspirate, as centrifugation differentially concentrates ASCs (Adipose-derived Stem Cells) in this fraction of the lipoaspirate [24]. The injecting cannula had a 3 mm diameter and was inserted via skin incision or intraorally with access through the mucosa. Small aliquots of fat were deposited linearly on the recipient sites, including the lips, nose (dorsum and alae), cheeks, and chins. Outcome measures: Patients were prospectively assessed before and after treatment. Preoperative assessment was performed during outpatient appointments or on the day of surgery prior to the operation. Postoperative assessments were performed at 12 months and at successive outpatient appointments at 12 months intervals. The assessment included (1) facial volume with 3D imaging, (2) mouth function, (3) psychological status and quality of life, (4) physician-based evaluation, and (5) patient-based satisfaction. Facial volumes and fat graft survival rate: Preoperative and post-operative 3-D photographs were performed using the static 3dMD system (3dMD, Atlanta, USA). Patients were scanned while sitting at 90° and were instructed to adopt a relaxed facial expression, with their lips resting and their teeth lightly in contact [25]. Volumetric differences were analyzed using the Vultus software. Pre- and post-treatment images were superimposed. To assure alignment precision, a root-mean-square (RMS) error, which indicates the differences between the two surfaces RMS, of maximum 0.5 mm was considered acceptable, as per the manufacturer guidelines (www.3dmd.com). After the images superimposition, the aesthetic units of interest (cheeks, nose, upper lip, lower lip, ACCEPTED and chin) were marked using fixed anatomical landmarks and the volume difference between the pre- and post-operative images was calculated with the “Volume Measurements” function. Following a comparison of the injected volume and the volumetric difference between the two surfaces (volume detected), the percentage of volume retained over time was computed. Mouth function: Mouth disability was assessed with the MHISS [26], a validated scale with 12 items each scored 0-4, with a total score ranging from 0 (minimal handicap) to 48 (maximal handicap). The 12 items are divided in three domains: mouth function, mouth dryness, and aesthetic concerns [26]. Psychological status and quality of life: The psychological aspect and quality of life were assessed using multiple validated measures. The Derriford Appearance Scale (DAS) measures the degree of psychological distress associated with physical appearance [27]. The Hospital Anxiety and Depression Scale (HADS) is a validated self-report questionnaire that identifies and quantifies anxiety disorders and depression [28]. The noticeability of the disfigurement measure consists of three Visual Analogic Scales (VAS) from 0 to10 in which the individual ranks the self-perceived noticeability of the disfigurement [29, 30]. The Brief Fear of Negative Evaluation Scale (BFNES) measures social anxiety disorder [31]. It is composed of 12 items related to worry or fearful cognition [32]. Physician-based satisfaction: Pre- and postoperative photographs of each patient were assessed and graded as ‘improved’ or ‘not improved. ” Improvements were further graded as ‘minor’ or ‘substantial.’ Improvement was defined as the overall facial volume restoration, orofacial disease severity, and mouth appearance. Patient-based satisfaction: At the final follow-up assessment, patients were asked to answer general questions regarding their satisfaction with the procedure. ACCEPTED Patient and Public Involvement (PPI): Patients with SSc actively participated in the selection of patient-reported outcome measures (PROMs) in this study in order to determine which features were more pertinent to them. Statistical analysis: Volumetric changes in fat grafts over time are presented as percentages. Intercomparisons between pre- and posttreatment values were analyzed statistically using a paired t-test with a nonparametric Wilcoxon matched-pairs signed rank test (Prism6 Software). Unrelated groups (i.e., lcSSc versus dcSSc) and groups presenting different variables (i.e., different number of treatments) were analyzed using non-paired t- tests (Prism6 Software). The tests were two-tailed, with a confidence interval of 95%. Means and standard deviations (SD) were calculated. Statistical significance was set at P <0.05. RESULTS Demographics Of the 93 included patients, 98% were female; average age at the time of surgery was 52 years (± 1.46); average disease duration was 12.27 (± 7.95) years; there was a nearly equal distribution of disease subsets, with 46% (n = 43) diagnosed with dcSSc and 54% (n = 50) with lcSSc. In addition, 63% (n = 59) of the patients had concurrent immunosuppression at the time of surgery and 38% (n = 34) did not. Overall, 89% (n = 83) of the patients presented with specific autoantibodies and 30% (n = 28) were associated with additional overlap syndromes (Table 1). ACCEPTED Operation details In total, 275 procedures were performed. Each patient received an average 2.96 (of 2.2) treatments. For each procedure, 11.9 cc (± 6) of fat was injected into the facial area (Table 2). Different aesthetic units were targeted, as follows: cheeks (3.8 ± 2.4), nose (1.8 ± 0.8), upper lip (2.9 ± 1.4), lower lip (2.6 ± 1.1) and chin (2. ± 0.9) (Table 2). Three patients presented moderate abdominal bruising that resolved within 14-21 days, and two developed postoperative wound infections respondent to oral antibiotic therapy. The average follow- up was 3.11 (± 1.73) years. Clinical Outcome Volumetric outcome and fat graft survival rate: Volumetric analysis showed that all facial aesthetic units retained a proportion of the injected volume to a lesser or greater extent, with an overall facial survival rate of 53.1% (± 0.17) at a follow-up of 3.11±1.73 years. Chin and lower lip presented the highest percentage of survival (59.5% and 56.5%, respectively). The nose had the lowest survival rate (39.4%), followed by the upper lip (50.3%), and cheeks (48.5%) (Table 2). The statistical significance (p values) of the difference in fat survival among the several facial aesthetic units is reported in Table 3. Subset analyses were performed according to the patient demographics (SDC 1). Significantly improved survival rates were found in patients who underwent five or more fat grafting procedures (73.1±0.08%) compared to those who underwent one or two (45.2±0.09% and 50.5±0.15%, respectively, P<0.05). No significant difference in fat survival rates was found between the disease subset (53.9±0.17% vs. 52.3±0.16%, P=0.44) and patients on concurrent immunosuppression compared to those not on immunosuppressive therapy (53.3±0.17% vs 52.7±0.16%, P=0.58). The presence of autoantibodies did not confer a significant difference in fat survival rates (P=0.330). Disease duration did not affect survival outcomes (P=0.876). ACCEPTED Mouth function outcome: A significant improvement in mouth function (P< 0.0001) was reported, with a median score of 28IQR 25-33) before and 23IQR 20-26) after surgery. The mouth opening subset represented 48% of the total mouth score improvement, followed by mouth dryness (33%) and aesthetic concerns (19%) (Table 4). Psychological status and quality of life outcomes: Patients reported a significant improvement in their psychological status following fat grafting (Table 5): physical appearance (DAS) (P<0.0001); self-perceived noticeability of disfigurement (VAS 1) (P<0.0001); perception of how noticeable the disfigurement was to other people (VAS 2) (P<0.0001); worrying about the noticeability of disfigurement (VAS 3) (P<0.0001); anxiety (P<0.0001), depression (P<0.0001) (HADS); and social anxiety (BFNE) (P<0.0001). Physician-based assessment: Out of the 93 patients included, 87% (n81) were considered improved. Of them, improvement was graded as substantial in 62% (n50) and minor in 38% (n31). Figures 1–3 illustrate the typical SSc-related facial features before and after fat grafting. These included microstomia and microcheilia (Figure 1A and 2A), subcutaneous tissue loss with overall taut facial tissues (Figure 1A), pointed nose (Figure 2A), and perioral radial furrows (Figure 3A), all of which improved after treatment (Figure 1B, 2B, 3B). Patient-based assessment: At the last follow-up, participants were queried regarding their satisfaction with the procedure, and 90% considered their face improved; 83% rated the outcome as good to excellent; 93% would undergo the procedure again; 97% would recommend the treatment to a friend/family member with a similar problem; and 93% considered they had no complications. The complications reported by patients (7%) were lumps, swelling, and bruising. DISCUSSION ACCEPTED In this study, we describe the long-term outcomes of fat grafting for correcting facial disfigurement in SSc. The rationale of this treatment is on one hand to increase the subcutaneous tissue bulk (‘volumetric effect’), and on the other hand to ameliorate the fibrotic tissues (‘regenerative effect’) 2. The latter is attributed to the ASCs secretome. We previously demonstrated that the surface phenotype and differentiation capacity of ASCs from patients with SSc are identical to those of healthy-matched ASCs. The proliferation and migration capacity of ASCs from patients with SSc was reduced, but they were capable of ex vivo culture and expansion 33. It has also been demonstrated that ASCs from patients with SSc have functionality similar to that of healthy controls in terms of senescence and mRNA profiles 21, 34. Previous studies investigating the paracrine effect of ASCs on SSc dermal myofibroblasts found that transforming growth factor (TGF- β1) and connective tissue growth factor (CTGF) secreted by SSc fibroblasts were significantly reduced when co-cultured with ASCs 21. These studies suggest that ASCs play a key anti-fibrotic role in SSs. Compared with prior studies on the use of lipofilling in facial SSc 35, 36, 37 this study presents multiple differences. First, the treatment was not limited to the perioral area, but was extended to different facial aesthetic units. Patients with scleroderma mainly complain of lip thinning and gradual difficulty in mouth opening; however patients present with pan-facial soft tissue changes associated with scleroderma with loss of nasal, cheek, and perioral soft tissue volume, as well as sclerotic changes to the lips, oral mucosa, and facial skin. We believe that targeting multiple facial aesthetic units achieves more natural results. In fact, we speculated that a paracrine antifibrotic effect might be exerted on the facial skin, allowing increased elasticity and tension release of the overall taut facial tissues, resulting in improved facial movement and a more natural aesthetic outcome. Clear communication with patients is ACCEPTED important for managing their expectations and informing them of physiological facial aging. In fact, while scleroderma is characterized by taut and hard skin, after pan-facial fat grafting, the replacement of soft tissue and improvement in skin elasticity can make the face more susceptible to normal aging. Therefore, it is important to discuss age-related changes in the facial soft tissues, including descent of the malar fat pad, laxity of the retaining ligaments of the mid-lateral face, and ptosis within the fascial-fatty layer and overlying dermis of the cheek mass (Figure 1B and 2B) 38, 39. Second, in this study, smaller amounts of fat were injected compared to previous reports. In the mouth, the average amount of fat graft was on average 5.6 (±1.3) cc, while in prior studies the range was 16-22 cc 35, 36, 37. Avoiding overcorrection is preferable for obtaining a balanced and long-lasting aesthetic outcome. Considering that the loss of a significant portion of the grafted volume has been the main criticism of this technique 22, the injection of small amounts is preferred to maximize the survival rate over time. This is consistent with the work of Eto et al., who investigated the fate of fat after grafting and proposed the ‘three zone principle’ [40, 41]. We performed smaller-volume injections and, if required, repeated the procedure multiple times, rather than injecting larger volumes at once. Given the severe fibrosis of the skin and underlying tissues in scleroderma, there is often insufficient room in the recipient site to accommodate a larger amount of fat graft. In our series we demonstrated that the adipose tissue injected in small amounts in multiple procedures survives better over time at an average follow up of 3.11 (± 1.73) years after the final treatment. Third, in this study the average number of treatments received was 2.95 (± 2.11), while the other groups reported only one treatment. We found that multiple sequential interventions produced a cumulative benefit, and is advisable to achieve a better outcome, with a significantly higher fat survival rate (p<0.05) in patients who received five or more fat ACCEPTED grafting procedures (73.1±0.08%). Randomized clinical trials are required to provide a clear evidence-based protocol and determine the optimal number of treatments. We used the standardized fat grafting technique described by Coleman 8. Several authors have challenged the value of this technique 42, 43, 44, 45, 46 or mixed it with platelet- rich plasma 47, 48. However, there is currently no evidence supporting the superiority of one technique over another in terms of the combined volumetric and antifibrotic effects. Hence, we chose to use the standardized technique to report a series treated with the same technique that did not change over the study period; and have a final byproduct that has been fully characterized, allowing future comparison and meta-analysis. Other methods may be explored to optimize the volumetric outcome by enhancing the fat graft survival rate. A recent randomized controlled pilot study on Localized Scleroderma showed that lipofilling enriched with ASCs presented a higher survival rate than conventional fat grafting and fat grafting enriched with Stromal Vascular Fraction (SVF) 49. However, both ASCs and SVF were obtained via collagenase digestion and are therefore not compliant with the regulations of most countries in the US and Europe. Strengths and limitations: The main strengths of the study include the objective assessment of the fat survival rate with 3D imaging, a non-invasive and cost-effective tool. Another aspect is the study power. SSc is a rare condition; hence, reports published to date have included small sample sizes. In our series, inclusion of a large cohort of patients was possible because our hospital is the national tertiary referral center for patients with SSc and the largest UK cohort. In addition, this study presents a longer follow-up of 3.11 years average (± 1.73) versus the 3 to 6 months previously reported 35, 36, 37. Finally, the present study presents a strong PPI component and robust PROMs. ACCEPTED Despite its strengths, this study has limitations. It is a single-arm study without a control group, and therefore a potential placebo effect cannot be excluded. In addition to that, the study was not blinded and this can have introduced bias in the patients-reported outcomes. In fact, it is well established that when individuals are aware they are being observed, they may change their normal behavior (Hawthorne effect), introducing a risk of bias 50. CONCLUSIONS This long-term study showed that fat grafting is effective in correcting the facial volumetric and fibrotic changes associated with scleroderma. Despite long-term follow-up, the definitive durability of this effect is unknown, and the optimal number of treatments must be determined. Although, this may be difficult because scleroderma is a chronic autoimmune disease and the pathological processes driving facial changes are ongoing. Clarification of the mechanism of the anti-fibrotic action of the technique, either through effector cells, multiple cells, or other mechanisms, is of significant interest for the development of an anti-fibrotic treatment for this and other diseases. ACKNOWLEDGEMENT: Preliminary results of this study were presented at the following conferences: Royal Society of Medicine 2018 in London (UK), and awarded the ‘Best Clinical Cases Prize’; International Federation for Adipose Therapeutic and Science (IFATS) Annual Meeting 2019 in Marseille (France), and awarded the ‘Best Presentation Prize’’. REFERENCES: 1. Van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification Criteria for Systemic Sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2013; 72: 1747-1755. 2. Almadori, A., Butler, P.E.M. (2022). Treatment of Scleroderma with Fat Grafting, PRP, and Adipose-Derived Stem Cells. In: Kalaaji, A. (eds) Plastic and Aesthetic ACCEPTED Regenerative Surgery and Fat Grafting. Springer, Cham. https://doi.org/10.1007/978-3-030-77455-4_32 3. Sobolewski P, Maślińska M, Wieczorek M, et al. Syst emic sclerosis – multidisciplinary disease: clinical features and treatment. 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Del Papa N, Caviggioli F, Sambataro D, Zaccara E, Vinci V, Di Luca G, et al. Autologous fat grafting in the treatment of fibrotic perioral changes in patients with systemic sclerosis. Cell Transplant. 2015;24(1):63-72. doi: 10.3727/096368914X674062. 37. Gheisari M, Ahmadzadeh A, Nobari N, Iranmanesh B, Mozafari N. Autologous Fat Grafting in the Treatment of Facial Scleroderma. Dermatol Res Pract. 2018 Aug 1;2018:6568016. doi: 10.1155/2018/6568016. 38. Yousif NJ: Changes of the midface with age. Clin Plast Surg 22:213, 1995 39. See MS, Roberts C, Nduka C. Age- and gravity-related changes in facial morphology: 3-dimensional analysis of facial morphology in mother-daughter pairs. Journal of Oral and Maxillofacial Surgery. 2008 Jul;66(7):1410-1416. ACCEPTED 40. Eto H, Kato H, Suga H, Aoi N, Doi K, Kuno S, et al. The fate of adipocytes after nonvascularized fat grafting: evidence of early death and replacement of adipocytes. Plastic and reconstructive surgery. 2012;129(5):1081-92. 41. Mashiko T, Yoshimura K. How does fat survive and remodel after grafting? Clin Plast Surg. 2015 Apr;42(2):181-90. doi: 10.1016/j.cps.2014.12.008. Epub 2015 Jan 29. PMID: 25827562. 42. Rohrich RJ , Sorokin ES, Brown SA. In search of improved fat transfer viability: a quantitative analysis of the role of centrifugation and harvest site. Plast Reconstr Surg. 2004;113:391–395. discussion 396–397 43. Asilian A, Siasat A, Iraji R. Comparison of fat maintenance in the face with cen- trifuge versus filtered and washed fat. J Res Med Sci. 2014;19:556–561. 44. Botti G, Pascali M, Botti C, et al. A clinical trial in facial fat grafting: filtered and washed versus centrifuged fat. Plast Reconstr Surg. 2011;127:2464–2473. 45. Serratrice N, Bruzzese L, Magalon J, Véran J, Giraudo L, Aboudou H, et al. New fat-derived products for treating skin-induced lesions of scleroderma in nude mice. Stem Cell Res Ther. 2014 Dec 17;5(6):138. 46. Tonnard P, Verpaele A, Peeters G, Hamdi M, Cornelissen M, Declercq H. Nanofat grafting: basic research and clinical applications. Plast Reconstr Surg. 2013 Oct;132(4):1017-26. 47. Philandrianos C, Magalon J, Daumas A, Veran J, Sabatier F, Magalon G, et al. Combined PRP and microfat graft for facial disability in systemic sclerosis. J Scleroderma Relat Disord 2017; 2(3):e7-e11 48. Virzì F, Bianca P, Giammona A, Apuzzo T, Di Franco S, Mangiapane LR, et al. Combined platelet-rich plasma and lipofilling treatment provides great improvement in facial skin-induced lesion regeneration for scleroderma patients. Stem Cell Res Ther. 2017 Oct 23;8(1):236. doi: 10.1186/s13287-017-0690-3. ACCEPTED 49. Wang C, Long X, Si L, Chen B, Zhang Y, Sun T, Zhang X, Zhao RC, Wang X. A pilot study on ex vivo expanded autologous adipose-derived stem cells of improving fat retention in localized scleroderma patients. Stem Cells Transl Med. 2021 Aug;10(8):1148-1156. doi: 10.1002/sctm.20-0419. Epub 2021 Apr 19. PMID: 33871949; PMCID: PMC8284772. 50. Demetriou C, Hu L, Smith TO, Hing CB. Hawthorne effect on surgical studies. ANZ J Surg. 2019 Dec;89(12):1567-1576. doi: 10.1111/ans.15475. Epub 2019 Oct 16. PMID: 31621178. ACCEPTED FIGURE / TABLE LEGEND: Table 1. Demographic data Table 2. Operation details and fat graft mean survival rate The table shows the injected volumes and the volumetric analysis performed. For each aesthetic unit, the volume injected and the volume difference detected by comparing the pre- and post-operative 3D scans were compared. Data are reported as the mean ± SD. The detected retention/survival rates were expressed as percentages. Volume analysis showed an overall good survival rate of the fat grafted in the face, although the percentage of fat survival varies in different aesthetic units. Table 3. Statistical difference in the percentage retention rate The table summarizes the statistical significance of the differences in fat survival between each facial aesthetic unit. The results are presented as p values (unpaired t-test). Statistically significant differences are highlighted in bold. Table 4. Mouth function outcome This table illustrates the results of the mouth function. Data are reported as mouth function overall and subdivided by each domain of the MHISS. Table 5. Psychological and quality of life outcome This table illustrates the psychological status and quality of life results assessed using different validated measures. Supplementary Digital Content 1. Effect of demographics on fat graft survival rate The table illustrates the survival rate (%) taking into consideration the demographic data. Results are represented in the different disease subsets (lcSSc versus dcSSc), in the different concurrent treatment subgroups (immunosuppression versus no immunosuppression), in the different number of lipofilling received, in the different age groups, in the presence of autoantibodies, and in the different lengths of disease duration. Figure 1. Cosmetic improvement after fat grafting - Case 1 ACCEPTED Representative patient with Systemic Sclerosis (dcSSc subset). At the time of the first treatment, the patient was 44 years old, and the disease duration was 22 years. The main features are microstomia, microcheilia, overall subcutaneous tissue loss, taut facial skin adherent to the underlying planes, and diminished facial expression (mask-like aspect). The shiny skin appearance is due to the skin being pulled taut over the underlying bone (A). The patient underwent three fat grafting procedures, and the average amount of subunit injection was (in ml) 2 in the cheeks, 2.17 in the nose, 4.83 in the upper lip, 4 in the lower lip, and 2 in the chin. After treatment, the overall skin became more elastic, resulting in a more relaxed facial expression. The lips show increased thickness and mouth closure is improved (B). The color map generated using the 3dMD system confirms volumetric enhancement in the perioral area after surgical treatment with fat grafting (C). Figure 2. Cosmetic improvement after fat grafting - Case 2 Representative patient with Systemic Sclerosis (dcSSc subset). At the time of the first treatment, the patient was 64 years old, and the disease duration was 18 years. The patient presented with microcheilia, microstomia, loss of the vermilion border of the lips, and resorption of subcutaneous tissue in the dorsum and alae of the nose, resulting in a typical scleroderma-pointed nose (A). The patient received nine fat grafting procedures and the average amount of subunit injection (in ml) 3.57 in the cheeks, 1.50 in the nose, 3.61 in the upper lip, 3.04 in the lower lip, 2.19 and chin. After treatment, the subcutaneous labial thickness increased, allowing normal mouth closure. The pointed nose was corrected with improved overall nasal appearance (B). Volumetric analysis confirmed a change in facial volume after surgical treatment with fat grafting, particularly in the inferior third of the face (C). Figure 3. Cosmetic improvement after fat grafting - Case 3 Representative patient with Systemic Sclerosis, (lcSSc subset). At the time of the first treatment, the patient was 73 years old, and the disease duration was 12 years. In this case, ACCEPTED the main characteristics were microcheilia and perioral radial furrows (A). After two sessions of fat grafting, the marked perioral furrows improved, with increased lip volume and reduced perioral wrinkles (B). Average amount of subunit injection was (in ml) 2.83 in the cheeks, 0.8 in the nose, 6.5 in the upper lip, 7 in the lower lip, 2.5 in the chin. Volumetric analysis showed volumetric augmentation of the cheeks, nose, chin, and lips (C). SDC 1. Effect of demographics on fat graft survival rate The table illustrates the survival rate (%) taking into consideration the demographic data. Results are represented in the different disease subsets (lcSSc versus dcSSc), in the different concurrent treatment subgroups (immunosuppression versus no immunosuppression), in the different number of lipofilling received, in the different age groups, in the presence of autoantibodies, and in the different lengths of disease duration. ACCEPTED Table 1. Demographic data Total number of patients (n) 93 Sex (n) Female (91) Male (2) Age at time of surgery (years; 51.70 ± 11.46 mean ± SD) Duration of disease at time of 12.27 ± 7.95 surgery (years; mean ± SD) Subset (n) DcSSc (43) LcSSc (50) Presence of autoantibodies (n) ANA negative (3); ANA positive, ENA negative (3); Specific autoantibodies (83) Specific Autoantibodies (n) Anti-Scl-70 (26); Anti-RNAP III (26); ACA (13); Anti-PM-Scl (5); Anti RNP (3); Anti-PL7 (3); Anti-CCP (3); Other (5) Overlap syndromes (n) Antiphospholipid syndrome (1); Systemic lupus erythematosus (3); Sjögren’s syndrome (7); Rheumatoid arthritis (3); Myositis (7); Inflammatory arthritis (4); Antisynthetase syndrome (2); Vasculitis (1) No (34) Yes (59): 1 x immunosuppressant (42); Concurrent immunosuppression 2 x immunosuppressants (16) (n) Major Drug Treatment (n) Mycophenolate mofetil (36); Hydroxychloroquine (23); Rituximab (3); Azathioprine (3); Methotrexate (8); Hydroxycarbamide (1) Abbreviations: dcSSc Diffuse cutaneous systemic sclerosis; lcSSc Limited cutaneous systemic sclerosis; Anti-Scl-70 Anti-topoisomerase I antibody; Anti-RNAP III Anti-RNA polymerase III antibody; ACA Anti-centromere antibody; Anti-PM-Scl Anti-exosome antibody; Anti-RNP Anti-ribonucleoprotein antibody; Anti-PL7 Anti-threonyl-tRNA synthetase antibody; Anti-CCP Anti-cyclic citrullinated peptide; Other (Anti-U3RNP Anti-fibrillarin antibody; Anti-Th/To Antibodies to Th/To ribonucleoprotein; Anti-hnRNP Anti-heterogenous nuclear ribonucleoproteins; Anti-Ro and Anti-La Anti-Sjögren’s-syndrome-related antigen A and B. ACCEPTED Table 2. Operation details and fat graft mean survival rate Aesthetic Unit Volume injected Volume detected Survival (cc; mean ± SD) (cc; mean ± SD) rate (%) Face overall 11.9 ± 6. 6.3 ± 2.5 53.1% 3.8 ± 2.4 1.8 ± 1.1 48.5% Cheeks 1.8 ± 0.8 0.7 ± 0.3 39.4% Nose Upper lip 2.9 ± 1.4 1.4 ± 0.9 50.3% Lower lip 2.6 ± 1.1 1.5 ± 0.7 56.5% Chin 2. ± 0.9 1.2 ± 0.7 59.5% Abbreviations: SD standard deviation ACCEPTED Table 3. Statistical difference (p values) in the percentage retention rate among the different facial aesthetic units Aesthetic Unit Cheeks Nose Upper lip Lower lip Chin Cheeks - 0,0011 0,5970 0,1169 0,0184 Nose 0,0011 - 0,0095 0,00001 0,000001 Upper lip 0,5970 - 0,0095 0,0531 0,0081 Lower lip 0,1169 0,00001 0,0531 - 0,3785 Chin 0,0184 0,000001 0,0081 0,3785 - ACCEPTED Table 4. Effect of fat grafting on mouth function outcome Score before fat graft Score after fat graft Score change Mouth assessment p value median (IQR) median (IQR) median (IQR) 28 (25-33) 23 (20-26) 5 (2.72-7.5) <0.0001 MHISS overall <0.0001 Mouth opening 13 (10-14) 9 (8-11) 3 (1-4) Mouth dryness <0.0001 10 (8-13) 9 (6-10) 1 (0-3) Aesthetic concern <0.0001 7 (5-8) 5.27 (4-6) 1 (0-2) Abbreviations: IQR Interquartile range MHISS Mouth Handicap in Systemic Sclerosis Paired t-test (nonparametric Wilcoxon matched-pairs signed rank test, Prism6 Software) ACCEPTED Table 5. Effect of fat grafting on psychological and quality of life outcome Score before fat graft Score after fat graft Score change Item p value median (IQR) median (IQR) median (IQR) DAS 47 (38-59) 40 (31-49) 6 (2-14) <0.0001 <0.0001 12 (9-17) 10 (8-12.5) 2 (0-4) HADS-A <0.0001 11 (7-17) 8 (6-12) 1 (-0.5-5) HADS-D <0.0001 VAS 1 8 (6-10) 7 (5-8) 1 (0-3) <0.0001 VAS 2 8 (6-10) 6 (5-8) 1 (0-3) VAS 3 9 (7-10) 7 (5.5-8) 1 (0-2.5) <0.0001 <0.0001 BFNES 36 (30-40.5) 32 (28-39) 3 (0-7) Abbreviations: IQR Interquartile range DAS Derriford Appearance Scale for satisfaction with appearance VAS Visual Analogue Scale for noticeability of disfigurement HADS-A Hospital Anxiety and Depression Scale - Anxiety HADS-D Hospital Anxiety and Depression Scale - Depression BFNES Brief Fear of Negative Evaluation Scale for social anxiety paired t-test (nonparametric Wilcoxon matched-pairs signed rank test, Prism6 Software) ACCEPTED Figure 1a ACCEPTED Figure 1b ACCEPTED Figure 1c ACCEPTED Figure 2a ACCEPTED Figure 2b ACCEPTED Figure 2c ACCEPTED Figure 3a ACCEPTED Figure 3b ACCEPTED Figure 3c ACCEPTED Supplementary Table 1. Effect of demographics on volumetric outcome. Face Cheeks Upper lip Lower lip Nose Chin overall (%) (%) (%) (%) (%) (%) All patients (93) 53.1 48.5 50.3 56.5 39.4 59.5 Total Values lcSSc (50) 53.9% 46.6 50 52,7 36.9 57.5 Disease subset dcSSc (43) 52.3% 50.3 50.6 61.2 41.9 52.3 p value 0.68 0.81 0.97 0.22 0.63 0.49 Concurrent Yes (59) 53.3 50.7 52.1 56.7 41.3 58.8 immunosuppression No (34) 52.7 45.1 47.6 56.2 35.8 60.5 p value 0.70 0.52 0.53 0.93 0.19 0.74 Number of fat 1 (26) 45.2 47.4 35.9 49.9 43.7 50.5 grafting 2 (26) 50.5 45.7 42.5 49.4 32.8 64.5 3 (15) 49.0 48.5 61.1 60.2 39.7 62.0 4 (11) 55.4 43.9 64.1 60.2 34.4 46.5 5+ (15) 73.1 57.7 64.8 72.6 47.1 70.1 Age 20-30 (5) 52.2 56.9 46.5 51.4 44.6 59.0 31-40 (7) 55.6 46.5 54.1 62.7 51.7 55.1 41-50 (28) 55.8 52.7 52.7 57.3 45.6 62.6 51-60 (22) 62.3 52.1 56.3 64.1 30.8 64.0 61+ (31) 52.4 54.1 46.5 52.5 41.9 57.1 Auto-ab Yes (90) 55.8 52.4 51.6 57.6 41.2 60.1 No (3) 64.0 63.2 37.5 51.3 72.7 65.8 p value 0.33 0.36 0.02 0.14 0.11 0.19 Auto-ab subset Anti-RNA P III (25) 53.0 51.5 48.8 57.1 42.4 56.2 Anti-Scl70 (26) 54.3 49.7 52.3 60.1 47.7 61.1 ACA (11) 53.3 52.1 46.8 53.5 29.5 64.3 Anti-PM/Scl (5) 62.2 47.8 58.9 62.2 46.4 49.7 Other (23) 60.2 57.7 54.5 56.3 34.2 63.1 0-5 (19) 57.9 55.1 53.4 54.1 40.4 61.9 Disease duration 6-10 (28) 57.0 54.9 54.3 62.6 40.9 66.0 11-20 (28) 57.8 50.6 50.8 60.2 39 57.2 21+ (18) 49.8 49.8 44.5 48.6 48.9 54.0 Abbreviations: dcSSc Diffuse cutaneous systemic sclerosis; lcSSc Limited cutaneous systemic sclerosis; Anti-Scl-70 Anti-topoisomerase I antibody; Anti-RNA P III Anti-RNA polymerase III antibody; ACA Anti-centromere antibody; Anti-PM-Scl Anti-exosome antibody; unpaired t-test (Prism6 Software) ACCEPTED http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Plastic & Reconstructive Surgery Wolters Kluwer Health

Long-term outcome of fat grafting to treat facial Systemic Sclerosis: a prospective cohort study

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Abstract

Plastic and Reconstructive Surgery Advance Online Article DOI: 10.1097/PRS.0000000000012111 Long-term outcome of fat grafting to treat facial Systemic Sclerosis: a prospective cohort study 1,2,3* 1,2,3 Aurora Almadori MBBS, MSc, MSc, PhD; Michelle Griffin MBBS, MSc ; Jeon 1,2,3 4 Hyun MBBS, MSc; Esther Hansen BSC(HONS), DCLINPSY; Christopher P Denton 5 1,2,3 PhD, FRCP ; Peter EM Butler MD, FRCSI, FRCS, FRCS (Plast) . UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College London, London, United Kingdom Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom Charles Wolfson Centre for Reconstructive Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom Clinical Psychology, Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom Center for Rheumatology, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom *Corresponding author: Dr Aurora Almadori, MBBS, MSc. PhD Pond St, London NW3 2QG, United Kingom [email protected] [email protected] Financial Disclosure Statement: The authors have nothing to disclose. No funding was received for this study. Short Running Head: Long-Term Results of Facial Fat Grafting in Systemic Sclerosis ACCEPTED Plain language summary: Systemic sclerosis is characterized by subcutaneous tissue loss, skin fibrosis, restricted facial movement, and mouth opening. Fat grafting is a minimally invasive procedure that restores facial volume and ameliorates skin fibrosis. We conducted a study of 93 patients with SSc who were treated with fat grafting. After an average of 2.96 fat grafting procedures, the fat survival rate was 53.1% at the 3.11-year follow-up. In addition, significant improvements in oral function and patient quality of life were observed. Facial fat grafting is an efficient method to restore facial volume and improve oral function and quality of life in patients with scleroderma. Keywords: Systemic sclerosis; Scleroderma; Fibrosis; Fat grafting; Fat transfer; Lipofilling; Lipotransfer; Adipose-derived stem cells; Regenerative medicine; Fat survival. Data Access Statement: All relevant data are within the paper. Additional data supporting this publication are available upon request. Author Contributions: The work constitutes part of AA’s PhD at University College of London. AA, EA, CD and PEB contributed to the design and implementation of the research; AA collected the data; AA and JK analyzed the results; AA wrote of the manuscript; PEB and CD conceived the original and supervised the project and revised the manuscript; MG only supervised student JH. Manuscript word count: 2,999 words (excluding references). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited ACCEPTED Abstract word count: 190. ABSTRACT Background Systemic Sclerosis (SSc) is characterized by subcutaneous tissue loss and dermal fibrosis, with limited facial movement and mouth opening. Fat grafting is a minimally invasive technique used to restore facial volume and improve skin fibrosis. Materials and methods A cohort of 93 patients were assessed using 3D imaging (3dMD) before and after fat grafting. Secondary outcomes included physician-based assessment, mouth function (MHISS), psychological status, quality of life (DAS, HADS, VAS, BFNES), and patient- based satisfaction. Results After an average of 2.96 (±2.2) sessions of fat grafting, with an injection volume of 11.9 cc (±6) in each session, the overall retention rate was 53.1% (±0.17) at an average follow-up of 3.11 (±1.73) years. Patients undergoing 5+ interventions presented a higher retention rate (73.1% ±0.08%) than those receiving one or two treatments (45.2% ±0.09 and 50.5% ±0.15 respectively) (P<0.05). Significant improvements were found in mouth function (P<0.0001) and quality of life (P<0.0001). Conclusion Facial fat grafting is an effective technique for restoring facial volume and improving oral function and quality of life in patients with scleroderma. This study presents the largest number of patients published to date with the longest follow-up period. ACCEPTED BACKGROUND Systemic Sclerosis (SSc) is a chronic autoimmune disease characterized by abnormal deposition of extracellular matrix (ECM), with progressive fibrosis [1, 2]. It is classified into two subsets: limited cutaneous SSc (lcSSc) if the skin fibrosis is confined to the face and extremities; and diffuse cutaneous SSc (dcSSc) if the skin fibrosis extends on the trunk and proximal parts of the limbs [1, 2]. Skin fibrosis and subcutaneous tissue loss are hallmark manifestations that are particularly noticeable in the face. Thickened and hardened skin is responsible for a taut and mask-like appearance with diminished facial expression. Typical orofacial features include subcutaneous tissue loss, fibrotic skin firmly attached to the underlying planes, nasal alar resorption resulting in a pointed nose, perioral wrinkles, and mouth changes [2]. The lips are usually thinned (microcheilia), and the skin around the mouth is stretched with deep perioral radial wrinkles, loss of the vermilion border of the lips, and narrowing of the oral line with reduced motility and opening (microstomia) [2]. When salivary gland function is impaired, dryness of the oral mucosa can be a feature (xerostomia) [2, 3]. Life-threatening aspects of the disease (heart, lung, renal involvement) have been a therapeutic priority, but non-lethal manifestations, like facial and hand impairments, are becoming increasingly important [4], as patients with scleroderma presents impaired quality of life, poor mental health, self-image issues, depression, anxiety, and lower perception of general health compared to healthy controls [2, 4, 5, 6, 7]. Fat grafting is minimally invasive surgery largely used in plastic surgery not only to fill contour deformities but also to improve skin fibrosis and scarring [2, 8, 9, 10, 11]. Its use in scleroderma has been successful in correcting volumetric deformities in localized scleroderma [12, 13, 14, 15] and improving mouth or hand function in SSc [16, 17, 18, 19, 20, 21]. However, studies published thus far present a short follow-up period; therefore, data on the durability of the effect in facial scleroderma are currently lacking. Evidence of ACCEPTED the use of lipotransfer for other applications has shown that it is associated with unpredictable long-term results due to volume resorption, which is currently the main limitation of this technique [22, 23]. This prospective cohort study aimed to assess the long-term volumetric outcomes after fat grafting in patients with SSc. METHODS Trial design: This study included 93 patients who met our inclusion criteria: 1) previous diagnosis of SSc irrespectively of the disease subset (dcSSc and lcSSc); 2) age < 18–75 years; 3) stabilized SSc disease (at least 2 years); 4) stable lung and cardiac functionality; 5) noticeable orofacial modification; and 6) verified orofacial dysfunction assessed with the Mouth Handicap in Systemic Sclerosis Scale (MHISS). The following categories were considered ineligible: 1) pregnant women; 2) individuals suffering from a widespread infection or cancer; and 3) those unable to give written, informed consent in English. Patients were selected from the Rheumatology and Plastic Surgery outpatient clinics. They were offered repeated procedures based on their clinical signs and symptoms with 12 months interval between the procedures. Ethical approval: This prospective study was conducted after approval from the institutional and regional ethical committees in charge (REC Hampshire B ref 16/SC/0669; R&D ref 10006). ACCEPTED Surgical technique: Fat was harvested using 15 mm × 3 mm disposable cannulas with two holes of 1 mm diameter. Donor sites were abdomen or medial thighs, where usually a sufficient amount of fat is present irrespectively of the patients’ disease severity or Body Mass Index (BMI). Lipoaspirate was centrifuged at 3000 rpm for 3 min [8]. We used only the distal 3/4 of the lipoaspirate, as centrifugation differentially concentrates ASCs (Adipose-derived Stem Cells) in this fraction of the lipoaspirate [24]. The injecting cannula had a 3 mm diameter and was inserted via skin incision or intraorally with access through the mucosa. Small aliquots of fat were deposited linearly on the recipient sites, including the lips, nose (dorsum and alae), cheeks, and chins. Outcome measures: Patients were prospectively assessed before and after treatment. Preoperative assessment was performed during outpatient appointments or on the day of surgery prior to the operation. Postoperative assessments were performed at 12 months and at successive outpatient appointments at 12 months intervals. The assessment included (1) facial volume with 3D imaging, (2) mouth function, (3) psychological status and quality of life, (4) physician-based evaluation, and (5) patient-based satisfaction. Facial volumes and fat graft survival rate: Preoperative and post-operative 3-D photographs were performed using the static 3dMD system (3dMD, Atlanta, USA). Patients were scanned while sitting at 90° and were instructed to adopt a relaxed facial expression, with their lips resting and their teeth lightly in contact [25]. Volumetric differences were analyzed using the Vultus software. Pre- and post-treatment images were superimposed. To assure alignment precision, a root-mean-square (RMS) error, which indicates the differences between the two surfaces RMS, of maximum 0.5 mm was considered acceptable, as per the manufacturer guidelines (www.3dmd.com). After the images superimposition, the aesthetic units of interest (cheeks, nose, upper lip, lower lip, ACCEPTED and chin) were marked using fixed anatomical landmarks and the volume difference between the pre- and post-operative images was calculated with the “Volume Measurements” function. Following a comparison of the injected volume and the volumetric difference between the two surfaces (volume detected), the percentage of volume retained over time was computed. Mouth function: Mouth disability was assessed with the MHISS [26], a validated scale with 12 items each scored 0-4, with a total score ranging from 0 (minimal handicap) to 48 (maximal handicap). The 12 items are divided in three domains: mouth function, mouth dryness, and aesthetic concerns [26]. Psychological status and quality of life: The psychological aspect and quality of life were assessed using multiple validated measures. The Derriford Appearance Scale (DAS) measures the degree of psychological distress associated with physical appearance [27]. The Hospital Anxiety and Depression Scale (HADS) is a validated self-report questionnaire that identifies and quantifies anxiety disorders and depression [28]. The noticeability of the disfigurement measure consists of three Visual Analogic Scales (VAS) from 0 to10 in which the individual ranks the self-perceived noticeability of the disfigurement [29, 30]. The Brief Fear of Negative Evaluation Scale (BFNES) measures social anxiety disorder [31]. It is composed of 12 items related to worry or fearful cognition [32]. Physician-based satisfaction: Pre- and postoperative photographs of each patient were assessed and graded as ‘improved’ or ‘not improved. ” Improvements were further graded as ‘minor’ or ‘substantial.’ Improvement was defined as the overall facial volume restoration, orofacial disease severity, and mouth appearance. Patient-based satisfaction: At the final follow-up assessment, patients were asked to answer general questions regarding their satisfaction with the procedure. ACCEPTED Patient and Public Involvement (PPI): Patients with SSc actively participated in the selection of patient-reported outcome measures (PROMs) in this study in order to determine which features were more pertinent to them. Statistical analysis: Volumetric changes in fat grafts over time are presented as percentages. Intercomparisons between pre- and posttreatment values were analyzed statistically using a paired t-test with a nonparametric Wilcoxon matched-pairs signed rank test (Prism6 Software). Unrelated groups (i.e., lcSSc versus dcSSc) and groups presenting different variables (i.e., different number of treatments) were analyzed using non-paired t- tests (Prism6 Software). The tests were two-tailed, with a confidence interval of 95%. Means and standard deviations (SD) were calculated. Statistical significance was set at P <0.05. RESULTS Demographics Of the 93 included patients, 98% were female; average age at the time of surgery was 52 years (± 1.46); average disease duration was 12.27 (± 7.95) years; there was a nearly equal distribution of disease subsets, with 46% (n = 43) diagnosed with dcSSc and 54% (n = 50) with lcSSc. In addition, 63% (n = 59) of the patients had concurrent immunosuppression at the time of surgery and 38% (n = 34) did not. Overall, 89% (n = 83) of the patients presented with specific autoantibodies and 30% (n = 28) were associated with additional overlap syndromes (Table 1). ACCEPTED Operation details In total, 275 procedures were performed. Each patient received an average 2.96 (of 2.2) treatments. For each procedure, 11.9 cc (± 6) of fat was injected into the facial area (Table 2). Different aesthetic units were targeted, as follows: cheeks (3.8 ± 2.4), nose (1.8 ± 0.8), upper lip (2.9 ± 1.4), lower lip (2.6 ± 1.1) and chin (2. ± 0.9) (Table 2). Three patients presented moderate abdominal bruising that resolved within 14-21 days, and two developed postoperative wound infections respondent to oral antibiotic therapy. The average follow- up was 3.11 (± 1.73) years. Clinical Outcome Volumetric outcome and fat graft survival rate: Volumetric analysis showed that all facial aesthetic units retained a proportion of the injected volume to a lesser or greater extent, with an overall facial survival rate of 53.1% (± 0.17) at a follow-up of 3.11±1.73 years. Chin and lower lip presented the highest percentage of survival (59.5% and 56.5%, respectively). The nose had the lowest survival rate (39.4%), followed by the upper lip (50.3%), and cheeks (48.5%) (Table 2). The statistical significance (p values) of the difference in fat survival among the several facial aesthetic units is reported in Table 3. Subset analyses were performed according to the patient demographics (SDC 1). Significantly improved survival rates were found in patients who underwent five or more fat grafting procedures (73.1±0.08%) compared to those who underwent one or two (45.2±0.09% and 50.5±0.15%, respectively, P<0.05). No significant difference in fat survival rates was found between the disease subset (53.9±0.17% vs. 52.3±0.16%, P=0.44) and patients on concurrent immunosuppression compared to those not on immunosuppressive therapy (53.3±0.17% vs 52.7±0.16%, P=0.58). The presence of autoantibodies did not confer a significant difference in fat survival rates (P=0.330). Disease duration did not affect survival outcomes (P=0.876). ACCEPTED Mouth function outcome: A significant improvement in mouth function (P< 0.0001) was reported, with a median score of 28IQR 25-33) before and 23IQR 20-26) after surgery. The mouth opening subset represented 48% of the total mouth score improvement, followed by mouth dryness (33%) and aesthetic concerns (19%) (Table 4). Psychological status and quality of life outcomes: Patients reported a significant improvement in their psychological status following fat grafting (Table 5): physical appearance (DAS) (P<0.0001); self-perceived noticeability of disfigurement (VAS 1) (P<0.0001); perception of how noticeable the disfigurement was to other people (VAS 2) (P<0.0001); worrying about the noticeability of disfigurement (VAS 3) (P<0.0001); anxiety (P<0.0001), depression (P<0.0001) (HADS); and social anxiety (BFNE) (P<0.0001). Physician-based assessment: Out of the 93 patients included, 87% (n81) were considered improved. Of them, improvement was graded as substantial in 62% (n50) and minor in 38% (n31). Figures 1–3 illustrate the typical SSc-related facial features before and after fat grafting. These included microstomia and microcheilia (Figure 1A and 2A), subcutaneous tissue loss with overall taut facial tissues (Figure 1A), pointed nose (Figure 2A), and perioral radial furrows (Figure 3A), all of which improved after treatment (Figure 1B, 2B, 3B). Patient-based assessment: At the last follow-up, participants were queried regarding their satisfaction with the procedure, and 90% considered their face improved; 83% rated the outcome as good to excellent; 93% would undergo the procedure again; 97% would recommend the treatment to a friend/family member with a similar problem; and 93% considered they had no complications. The complications reported by patients (7%) were lumps, swelling, and bruising. DISCUSSION ACCEPTED In this study, we describe the long-term outcomes of fat grafting for correcting facial disfigurement in SSc. The rationale of this treatment is on one hand to increase the subcutaneous tissue bulk (‘volumetric effect’), and on the other hand to ameliorate the fibrotic tissues (‘regenerative effect’) 2. The latter is attributed to the ASCs secretome. We previously demonstrated that the surface phenotype and differentiation capacity of ASCs from patients with SSc are identical to those of healthy-matched ASCs. The proliferation and migration capacity of ASCs from patients with SSc was reduced, but they were capable of ex vivo culture and expansion 33. It has also been demonstrated that ASCs from patients with SSc have functionality similar to that of healthy controls in terms of senescence and mRNA profiles 21, 34. Previous studies investigating the paracrine effect of ASCs on SSc dermal myofibroblasts found that transforming growth factor (TGF- β1) and connective tissue growth factor (CTGF) secreted by SSc fibroblasts were significantly reduced when co-cultured with ASCs 21. These studies suggest that ASCs play a key anti-fibrotic role in SSs. Compared with prior studies on the use of lipofilling in facial SSc 35, 36, 37 this study presents multiple differences. First, the treatment was not limited to the perioral area, but was extended to different facial aesthetic units. Patients with scleroderma mainly complain of lip thinning and gradual difficulty in mouth opening; however patients present with pan-facial soft tissue changes associated with scleroderma with loss of nasal, cheek, and perioral soft tissue volume, as well as sclerotic changes to the lips, oral mucosa, and facial skin. We believe that targeting multiple facial aesthetic units achieves more natural results. In fact, we speculated that a paracrine antifibrotic effect might be exerted on the facial skin, allowing increased elasticity and tension release of the overall taut facial tissues, resulting in improved facial movement and a more natural aesthetic outcome. Clear communication with patients is ACCEPTED important for managing their expectations and informing them of physiological facial aging. In fact, while scleroderma is characterized by taut and hard skin, after pan-facial fat grafting, the replacement of soft tissue and improvement in skin elasticity can make the face more susceptible to normal aging. Therefore, it is important to discuss age-related changes in the facial soft tissues, including descent of the malar fat pad, laxity of the retaining ligaments of the mid-lateral face, and ptosis within the fascial-fatty layer and overlying dermis of the cheek mass (Figure 1B and 2B) 38, 39. Second, in this study, smaller amounts of fat were injected compared to previous reports. In the mouth, the average amount of fat graft was on average 5.6 (±1.3) cc, while in prior studies the range was 16-22 cc 35, 36, 37. Avoiding overcorrection is preferable for obtaining a balanced and long-lasting aesthetic outcome. Considering that the loss of a significant portion of the grafted volume has been the main criticism of this technique 22, the injection of small amounts is preferred to maximize the survival rate over time. This is consistent with the work of Eto et al., who investigated the fate of fat after grafting and proposed the ‘three zone principle’ [40, 41]. We performed smaller-volume injections and, if required, repeated the procedure multiple times, rather than injecting larger volumes at once. Given the severe fibrosis of the skin and underlying tissues in scleroderma, there is often insufficient room in the recipient site to accommodate a larger amount of fat graft. In our series we demonstrated that the adipose tissue injected in small amounts in multiple procedures survives better over time at an average follow up of 3.11 (± 1.73) years after the final treatment. Third, in this study the average number of treatments received was 2.95 (± 2.11), while the other groups reported only one treatment. We found that multiple sequential interventions produced a cumulative benefit, and is advisable to achieve a better outcome, with a significantly higher fat survival rate (p<0.05) in patients who received five or more fat ACCEPTED grafting procedures (73.1±0.08%). Randomized clinical trials are required to provide a clear evidence-based protocol and determine the optimal number of treatments. We used the standardized fat grafting technique described by Coleman 8. Several authors have challenged the value of this technique 42, 43, 44, 45, 46 or mixed it with platelet- rich plasma 47, 48. However, there is currently no evidence supporting the superiority of one technique over another in terms of the combined volumetric and antifibrotic effects. Hence, we chose to use the standardized technique to report a series treated with the same technique that did not change over the study period; and have a final byproduct that has been fully characterized, allowing future comparison and meta-analysis. Other methods may be explored to optimize the volumetric outcome by enhancing the fat graft survival rate. A recent randomized controlled pilot study on Localized Scleroderma showed that lipofilling enriched with ASCs presented a higher survival rate than conventional fat grafting and fat grafting enriched with Stromal Vascular Fraction (SVF) 49. However, both ASCs and SVF were obtained via collagenase digestion and are therefore not compliant with the regulations of most countries in the US and Europe. Strengths and limitations: The main strengths of the study include the objective assessment of the fat survival rate with 3D imaging, a non-invasive and cost-effective tool. Another aspect is the study power. SSc is a rare condition; hence, reports published to date have included small sample sizes. In our series, inclusion of a large cohort of patients was possible because our hospital is the national tertiary referral center for patients with SSc and the largest UK cohort. In addition, this study presents a longer follow-up of 3.11 years average (± 1.73) versus the 3 to 6 months previously reported 35, 36, 37. Finally, the present study presents a strong PPI component and robust PROMs. ACCEPTED Despite its strengths, this study has limitations. It is a single-arm study without a control group, and therefore a potential placebo effect cannot be excluded. In addition to that, the study was not blinded and this can have introduced bias in the patients-reported outcomes. In fact, it is well established that when individuals are aware they are being observed, they may change their normal behavior (Hawthorne effect), introducing a risk of bias 50. CONCLUSIONS This long-term study showed that fat grafting is effective in correcting the facial volumetric and fibrotic changes associated with scleroderma. Despite long-term follow-up, the definitive durability of this effect is unknown, and the optimal number of treatments must be determined. Although, this may be difficult because scleroderma is a chronic autoimmune disease and the pathological processes driving facial changes are ongoing. Clarification of the mechanism of the anti-fibrotic action of the technique, either through effector cells, multiple cells, or other mechanisms, is of significant interest for the development of an anti-fibrotic treatment for this and other diseases. ACKNOWLEDGEMENT: Preliminary results of this study were presented at the following conferences: Royal Society of Medicine 2018 in London (UK), and awarded the ‘Best Clinical Cases Prize’; International Federation for Adipose Therapeutic and Science (IFATS) Annual Meeting 2019 in Marseille (France), and awarded the ‘Best Presentation Prize’’. REFERENCES: 1. Van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification Criteria for Systemic Sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2013; 72: 1747-1755. 2. Almadori, A., Butler, P.E.M. (2022). Treatment of Scleroderma with Fat Grafting, PRP, and Adipose-Derived Stem Cells. In: Kalaaji, A. (eds) Plastic and Aesthetic ACCEPTED Regenerative Surgery and Fat Grafting. Springer, Cham. https://doi.org/10.1007/978-3-030-77455-4_32 3. Sobolewski P, Maślińska M, Wieczorek M, et al. Syst emic sclerosis – multidisciplinary disease: clinical features and treatment. 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PMID: 33871949; PMCID: PMC8284772. 50. Demetriou C, Hu L, Smith TO, Hing CB. Hawthorne effect on surgical studies. ANZ J Surg. 2019 Dec;89(12):1567-1576. doi: 10.1111/ans.15475. Epub 2019 Oct 16. PMID: 31621178. ACCEPTED FIGURE / TABLE LEGEND: Table 1. Demographic data Table 2. Operation details and fat graft mean survival rate The table shows the injected volumes and the volumetric analysis performed. For each aesthetic unit, the volume injected and the volume difference detected by comparing the pre- and post-operative 3D scans were compared. Data are reported as the mean ± SD. The detected retention/survival rates were expressed as percentages. Volume analysis showed an overall good survival rate of the fat grafted in the face, although the percentage of fat survival varies in different aesthetic units. Table 3. Statistical difference in the percentage retention rate The table summarizes the statistical significance of the differences in fat survival between each facial aesthetic unit. The results are presented as p values (unpaired t-test). Statistically significant differences are highlighted in bold. Table 4. Mouth function outcome This table illustrates the results of the mouth function. Data are reported as mouth function overall and subdivided by each domain of the MHISS. Table 5. Psychological and quality of life outcome This table illustrates the psychological status and quality of life results assessed using different validated measures. Supplementary Digital Content 1. Effect of demographics on fat graft survival rate The table illustrates the survival rate (%) taking into consideration the demographic data. Results are represented in the different disease subsets (lcSSc versus dcSSc), in the different concurrent treatment subgroups (immunosuppression versus no immunosuppression), in the different number of lipofilling received, in the different age groups, in the presence of autoantibodies, and in the different lengths of disease duration. Figure 1. Cosmetic improvement after fat grafting - Case 1 ACCEPTED Representative patient with Systemic Sclerosis (dcSSc subset). At the time of the first treatment, the patient was 44 years old, and the disease duration was 22 years. The main features are microstomia, microcheilia, overall subcutaneous tissue loss, taut facial skin adherent to the underlying planes, and diminished facial expression (mask-like aspect). The shiny skin appearance is due to the skin being pulled taut over the underlying bone (A). The patient underwent three fat grafting procedures, and the average amount of subunit injection was (in ml) 2 in the cheeks, 2.17 in the nose, 4.83 in the upper lip, 4 in the lower lip, and 2 in the chin. After treatment, the overall skin became more elastic, resulting in a more relaxed facial expression. The lips show increased thickness and mouth closure is improved (B). The color map generated using the 3dMD system confirms volumetric enhancement in the perioral area after surgical treatment with fat grafting (C). Figure 2. Cosmetic improvement after fat grafting - Case 2 Representative patient with Systemic Sclerosis (dcSSc subset). At the time of the first treatment, the patient was 64 years old, and the disease duration was 18 years. The patient presented with microcheilia, microstomia, loss of the vermilion border of the lips, and resorption of subcutaneous tissue in the dorsum and alae of the nose, resulting in a typical scleroderma-pointed nose (A). The patient received nine fat grafting procedures and the average amount of subunit injection (in ml) 3.57 in the cheeks, 1.50 in the nose, 3.61 in the upper lip, 3.04 in the lower lip, 2.19 and chin. After treatment, the subcutaneous labial thickness increased, allowing normal mouth closure. The pointed nose was corrected with improved overall nasal appearance (B). Volumetric analysis confirmed a change in facial volume after surgical treatment with fat grafting, particularly in the inferior third of the face (C). Figure 3. Cosmetic improvement after fat grafting - Case 3 Representative patient with Systemic Sclerosis, (lcSSc subset). At the time of the first treatment, the patient was 73 years old, and the disease duration was 12 years. In this case, ACCEPTED the main characteristics were microcheilia and perioral radial furrows (A). After two sessions of fat grafting, the marked perioral furrows improved, with increased lip volume and reduced perioral wrinkles (B). Average amount of subunit injection was (in ml) 2.83 in the cheeks, 0.8 in the nose, 6.5 in the upper lip, 7 in the lower lip, 2.5 in the chin. Volumetric analysis showed volumetric augmentation of the cheeks, nose, chin, and lips (C). SDC 1. Effect of demographics on fat graft survival rate The table illustrates the survival rate (%) taking into consideration the demographic data. Results are represented in the different disease subsets (lcSSc versus dcSSc), in the different concurrent treatment subgroups (immunosuppression versus no immunosuppression), in the different number of lipofilling received, in the different age groups, in the presence of autoantibodies, and in the different lengths of disease duration. ACCEPTED Table 1. Demographic data Total number of patients (n) 93 Sex (n) Female (91) Male (2) Age at time of surgery (years; 51.70 ± 11.46 mean ± SD) Duration of disease at time of 12.27 ± 7.95 surgery (years; mean ± SD) Subset (n) DcSSc (43) LcSSc (50) Presence of autoantibodies (n) ANA negative (3); ANA positive, ENA negative (3); Specific autoantibodies (83) Specific Autoantibodies (n) Anti-Scl-70 (26); Anti-RNAP III (26); ACA (13); Anti-PM-Scl (5); Anti RNP (3); Anti-PL7 (3); Anti-CCP (3); Other (5) Overlap syndromes (n) Antiphospholipid syndrome (1); Systemic lupus erythematosus (3); Sjögren’s syndrome (7); Rheumatoid arthritis (3); Myositis (7); Inflammatory arthritis (4); Antisynthetase syndrome (2); Vasculitis (1) No (34) Yes (59): 1 x immunosuppressant (42); Concurrent immunosuppression 2 x immunosuppressants (16) (n) Major Drug Treatment (n) Mycophenolate mofetil (36); Hydroxychloroquine (23); Rituximab (3); Azathioprine (3); Methotrexate (8); Hydroxycarbamide (1) Abbreviations: dcSSc Diffuse cutaneous systemic sclerosis; lcSSc Limited cutaneous systemic sclerosis; Anti-Scl-70 Anti-topoisomerase I antibody; Anti-RNAP III Anti-RNA polymerase III antibody; ACA Anti-centromere antibody; Anti-PM-Scl Anti-exosome antibody; Anti-RNP Anti-ribonucleoprotein antibody; Anti-PL7 Anti-threonyl-tRNA synthetase antibody; Anti-CCP Anti-cyclic citrullinated peptide; Other (Anti-U3RNP Anti-fibrillarin antibody; Anti-Th/To Antibodies to Th/To ribonucleoprotein; Anti-hnRNP Anti-heterogenous nuclear ribonucleoproteins; Anti-Ro and Anti-La Anti-Sjögren’s-syndrome-related antigen A and B. ACCEPTED Table 2. Operation details and fat graft mean survival rate Aesthetic Unit Volume injected Volume detected Survival (cc; mean ± SD) (cc; mean ± SD) rate (%) Face overall 11.9 ± 6. 6.3 ± 2.5 53.1% 3.8 ± 2.4 1.8 ± 1.1 48.5% Cheeks 1.8 ± 0.8 0.7 ± 0.3 39.4% Nose Upper lip 2.9 ± 1.4 1.4 ± 0.9 50.3% Lower lip 2.6 ± 1.1 1.5 ± 0.7 56.5% Chin 2. ± 0.9 1.2 ± 0.7 59.5% Abbreviations: SD standard deviation ACCEPTED Table 3. Statistical difference (p values) in the percentage retention rate among the different facial aesthetic units Aesthetic Unit Cheeks Nose Upper lip Lower lip Chin Cheeks - 0,0011 0,5970 0,1169 0,0184 Nose 0,0011 - 0,0095 0,00001 0,000001 Upper lip 0,5970 - 0,0095 0,0531 0,0081 Lower lip 0,1169 0,00001 0,0531 - 0,3785 Chin 0,0184 0,000001 0,0081 0,3785 - ACCEPTED Table 4. Effect of fat grafting on mouth function outcome Score before fat graft Score after fat graft Score change Mouth assessment p value median (IQR) median (IQR) median (IQR) 28 (25-33) 23 (20-26) 5 (2.72-7.5) <0.0001 MHISS overall <0.0001 Mouth opening 13 (10-14) 9 (8-11) 3 (1-4) Mouth dryness <0.0001 10 (8-13) 9 (6-10) 1 (0-3) Aesthetic concern <0.0001 7 (5-8) 5.27 (4-6) 1 (0-2) Abbreviations: IQR Interquartile range MHISS Mouth Handicap in Systemic Sclerosis Paired t-test (nonparametric Wilcoxon matched-pairs signed rank test, Prism6 Software) ACCEPTED Table 5. Effect of fat grafting on psychological and quality of life outcome Score before fat graft Score after fat graft Score change Item p value median (IQR) median (IQR) median (IQR) DAS 47 (38-59) 40 (31-49) 6 (2-14) <0.0001 <0.0001 12 (9-17) 10 (8-12.5) 2 (0-4) HADS-A <0.0001 11 (7-17) 8 (6-12) 1 (-0.5-5) HADS-D <0.0001 VAS 1 8 (6-10) 7 (5-8) 1 (0-3) <0.0001 VAS 2 8 (6-10) 6 (5-8) 1 (0-3) VAS 3 9 (7-10) 7 (5.5-8) 1 (0-2.5) <0.0001 <0.0001 BFNES 36 (30-40.5) 32 (28-39) 3 (0-7) Abbreviations: IQR Interquartile range DAS Derriford Appearance Scale for satisfaction with appearance VAS Visual Analogue Scale for noticeability of disfigurement HADS-A Hospital Anxiety and Depression Scale - Anxiety HADS-D Hospital Anxiety and Depression Scale - Depression BFNES Brief Fear of Negative Evaluation Scale for social anxiety paired t-test (nonparametric Wilcoxon matched-pairs signed rank test, Prism6 Software) ACCEPTED Figure 1a ACCEPTED Figure 1b ACCEPTED Figure 1c ACCEPTED Figure 2a ACCEPTED Figure 2b ACCEPTED Figure 2c ACCEPTED Figure 3a ACCEPTED Figure 3b ACCEPTED Figure 3c ACCEPTED Supplementary Table 1. Effect of demographics on volumetric outcome. Face Cheeks Upper lip Lower lip Nose Chin overall (%) (%) (%) (%) (%) (%) All patients (93) 53.1 48.5 50.3 56.5 39.4 59.5 Total Values lcSSc (50) 53.9% 46.6 50 52,7 36.9 57.5 Disease subset dcSSc (43) 52.3% 50.3 50.6 61.2 41.9 52.3 p value 0.68 0.81 0.97 0.22 0.63 0.49 Concurrent Yes (59) 53.3 50.7 52.1 56.7 41.3 58.8 immunosuppression No (34) 52.7 45.1 47.6 56.2 35.8 60.5 p value 0.70 0.52 0.53 0.93 0.19 0.74 Number of fat 1 (26) 45.2 47.4 35.9 49.9 43.7 50.5 grafting 2 (26) 50.5 45.7 42.5 49.4 32.8 64.5 3 (15) 49.0 48.5 61.1 60.2 39.7 62.0 4 (11) 55.4 43.9 64.1 60.2 34.4 46.5 5+ (15) 73.1 57.7 64.8 72.6 47.1 70.1 Age 20-30 (5) 52.2 56.9 46.5 51.4 44.6 59.0 31-40 (7) 55.6 46.5 54.1 62.7 51.7 55.1 41-50 (28) 55.8 52.7 52.7 57.3 45.6 62.6 51-60 (22) 62.3 52.1 56.3 64.1 30.8 64.0 61+ (31) 52.4 54.1 46.5 52.5 41.9 57.1 Auto-ab Yes (90) 55.8 52.4 51.6 57.6 41.2 60.1 No (3) 64.0 63.2 37.5 51.3 72.7 65.8 p value 0.33 0.36 0.02 0.14 0.11 0.19 Auto-ab subset Anti-RNA P III (25) 53.0 51.5 48.8 57.1 42.4 56.2 Anti-Scl70 (26) 54.3 49.7 52.3 60.1 47.7 61.1 ACA (11) 53.3 52.1 46.8 53.5 29.5 64.3 Anti-PM/Scl (5) 62.2 47.8 58.9 62.2 46.4 49.7 Other (23) 60.2 57.7 54.5 56.3 34.2 63.1 0-5 (19) 57.9 55.1 53.4 54.1 40.4 61.9 Disease duration 6-10 (28) 57.0 54.9 54.3 62.6 40.9 66.0 11-20 (28) 57.8 50.6 50.8 60.2 39 57.2 21+ (18) 49.8 49.8 44.5 48.6 48.9 54.0 Abbreviations: dcSSc Diffuse cutaneous systemic sclerosis; lcSSc Limited cutaneous systemic sclerosis; Anti-Scl-70 Anti-topoisomerase I antibody; Anti-RNA P III Anti-RNA polymerase III antibody; ACA Anti-centromere antibody; Anti-PM-Scl Anti-exosome antibody; unpaired t-test (Prism6 Software) ACCEPTED

Journal

Plastic & Reconstructive Surgery – Wolters Kluwer Health

Published: Mar 25, 2025

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