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Fat Grafting for the Treatment of Scleroderma

Strong, Amy L. M.D., Ph.D.; Rubin, J. Peter M.D.; Kozlow, Jeffrey H. M.D., M.S.; Cederna, Paul S. M.D.

Plastic and Reconstructive Surgery: December 2019 - Volume 144 - Issue 6 - p 1498-1507
doi: 10.1097/PRS.0000000000006291
Plastic Surgery Focus: Special Topics
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Background: Scleroderma is a chronic connective tissue disease that results in fibrosis of the skin and internal organs. Although internal organ involvement corresponds with poor prognosis, systemic agents are effective at improving the effects of scleroderma on internal organs. In contrast, skin manifestations are universally present in all patients diagnosed with scleroderma, yet no systemic agents have been shown to be successful. Fat grafting has been shown to improve skin quality and improve contour irregularities and may be helpful in the treatment of patients with scleroderma.

Methods: The authors performed a thorough review of the pathophysiology of scleroderma and the current treatment options for scleroderma. The efficacy of fat grafting for the treatment of scleroderma and the mechanism by which fat grafting improves outcomes was also discussed.

Results: Scleroderma is characterized by chronic inflammation and vascular compromise that leads to fibrosis of the skin and internal organs. Fat grafting has recently been the focus of significant basic science research. It has been shown to reduce inflammation, reduce fibrosis by limiting extracellular matrix proteins and increasing collagenase activity, and provide structural support through stem cell proliferation and differentiation. The adipocytes, adipose stem cells, endothelial cells, and vascular smooth muscle cells in the processed fat likely contribute to the effectiveness of this treatment.

Conclusions: Fat grafting in scleroderma patients likely improves skin manifestations by recreating fullness, correcting contour deformities, and improving skin quality. The injected fat provides a mixture of cells that influences the recipient site, resulting in improved outcomes.

Ann Arbor, Mich.; and Pittsburgh, Pa

From the Section of Plastic and Reconstructive Surgery and the Department of Biomedical Engineering, University of Michigan; and the Department of Plastic Surgery and the McGowan Institute for Regenerative Medicine, University of Pittsburgh.

Received for publication October 8, 2018; accepted April 16, 2019.

Disclosure:None of the authors has a financial interest to declare in relation to the content of this article.

Paul S. Cederna, M.D., Section of Plastic and Reconstructive Surgery, University of Michigan, 2130 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, Mich. 48109-0340, cederna@med.umich.edu

Scleroderma is a connective tissue disease characterized by autoantibody production, chronic inflammation, small vessel vasculopathy, and excessive collagen deposition in the skin and internal organs. Scleroderma is divided based on disease extent into localized scleroderma and systemic scleroderma. Localized scleroderma is subdivided into subtypes based on location, degree of involvement, and level of connective tissue involvement.1 In contrast, systemic scleroderma is an extensive disease that involves both skin and soft-tissues changes and severe internal organ damage.2

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PATHOPHYSIOLOGY

Scleroderma is associated with widespread inflammation in the skin and subcutaneous tissue, with visceral organ involvement in systemic scleroderma. In the early stages of scleroderma, the cellular infiltrates, consisting mostly of type 2 helper T cells, display markers of activation and exhibit oligoclonal expansion.3,4 These characteristics parallel the robust increase in serum levels of cytokine transforming growth factor-beta (TGF-β), platelet-derived growth factor, and interleukin-1.5–7 TGF-β has a cascading effect by activating additional downstream inflammatory mediators that further promote inflammation.8–10 Similarly, platelet-derived growth factor activates many downstream targets that enhance the inflammatory response.11,12 Recent analyses of interleukin-1 have also demonstrated higher concentrations in scleroderma patients and play a key role in inflammation.13,14 Together, the activation of type 2 helper T cells results in the release of potent inflammatory cytokines and widespread inflammation (Fig. 1).

Fig. 1.

Fig. 1.

Following the initial inflammation, vascular injury ensues and involves injury to small vessels.15,16 In early lesions, there is an increase in endothelial cell apoptosis, leading to large gaps between endothelial cells, loss of endothelial lining integrity, and destruction of basal lamina–like layers.17–19 The vascular damage results in the loss of capillaries.20 Simultaneously, fibrotic intimal hyperplasia and smooth muscle hypertrophy occurs in arteries and arterioles, resulting in progressive blood vessel narrowing. The vasculopathy results in insufficient blood flow, causing severe and chronic hypoxia in internal organs and vasospasm and ischemic pain in the extremities. Poor blood flow to the extremities and reduced blood flow to vital organs in scleroderma results in ischemic pain, pulmonary arterial hyperplasia, and renal crisis.

The inflammatory response and vascular compromise progresses to skin fibrosis. Fibrosis is initiated with the conversion of fibroblasts into myofibroblasts. This conversion is associated with the overexpression of cytokines, including alpha smooth muscle actin, TGF-β, monocyte chemoattractant protein 1, and toll-like receptors.21–23 The transformed myofibroblasts orchestrate the production, deposition, and remodeling of collagens and other extracellular matrix components.24,25 Fibrosis in the skin begins in the lower dermis and upper subcutaneous layer and spreads to the dermal appendages, reticular structure, and rete ridges. Clinically, patients demonstrate skin thickening, loss of hair follicles, and dry skin.

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CLINICAL MANIFESTATIONS

Skin

Skin manifestations associated with localized scleroderma and systemic scleroderma are vastly different based on the subtype. Among the subtypes of localized scleroderma, linear scleroderma is most easily recognized as linear deformity that extends from the skin down to the bone in a unilateral fashion along a dermatome.26 The other forms of scleroderma, including plaque morphea, deep morphea, and generalized morphea, present with one or more lesions over the body that vary in type and depth of involvement.27 Systemic scleroderma, in contrast, is associated with hardening of the skin, disappearance of mimic folds, thinning of lips, loss of facial hair, and the presence of deep wrinkles in the upper and lower face.28 The extent of the facial involvement determines the loss of expressivity.28 Sclerosis of the perioral soft tissue results in microstomia, which impairs speech, mastication, mandibular movement, and proper oral hygiene.29,30 Skin manifestations of systemic scleroderma in the hand include skin sclerosis, calcinosis, Raynaud phenomenon, and digital ulcers.31,32 Thus, the skin involvement can be devastating from functional and cosmetic perspectives in localized and systemic scleroderma.

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Joints

Joint involvement is commonly observed in systemic scleroderma, and the extent and location of the skin, tendon, and capsule involvement determines severity. Limited cutaneous systemic scleroderma is characterized by skin fibrosis of the fingers and joints in the hands. Diffuse cutaneous systemic scleroderma affects the trunk, upper extremities, and lower extremities. Irrespective of the extent of involvement, the most common disease manifestations of systemic sclerosis is noted in the hand.33 Scleroderma patients develop symmetric, polyarticular synovitis of the metacarpophalangeal and proximal interphalangeal joints in a rheumatoid arthritis–like pattern. Although joint contractures of the hand are common, distortion of the proximal interphalangeal joint is the most common.34 Peritendinous sclerosis leads to tendon shortening and joint destruction, resulting in ankylosis.35

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Internal Organs

Internal organs, including the lungs, kidneys, and esophagus, can be compromised in diffuse cutaneous systemic scleroderma. Pulmonary fibrosis is common in scleroderma patients and is often the cause of pulmonary arterial hypertension and right heart failure in scleroderma patients.36 Diffuse scleroderma can also impact the gastrointestinal system, resulting in reflux esophagitis, esophageal strictures, Barrett esophagus, and esophageal and gastric dysmotility. Renal involvement in the form of hyperreninemia, azotemia, microangiopathic hemolytic anemia, and malignant hypertension is also common and considered a poor prognostic factor. Thus, systemic scleroderma affects many organs with an array of clinical presentations.

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CURRENT TREATMENT OPTIONS

As the cause of scleroderma remains unknown, the treatment of this disease remains a great challenge to clinicians. Treatment regimens are directed at improving circulation with vasodilators and antiplatelet therapy, preventing synthesis and release of harmful cytokines with immunosuppressants, and reducing fibrosis with collagen synthesis inhibitors or collagenase.37 However, the use of these agents is not without severe side effects, including systemic toxicity, chronic immune suppression, and bleeding. Furthermore, their efficacy in treating cutaneous manifestations of scleroderma is limited. Inadequate perfusion of these medications to the dermis because of the underlying scleroderma limits their efficacy. Moreover, these medications do not have regenerative properties and have only the potential to halt disease progression. Therefore, identification alternative treatment options for scleroderma are necessary.

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ROLE OF FAT GRAFTING FOR THE TREATMENT OF SCLERODERMA

Autologous fat grafting has recently gained significant attention because of its effectiveness at recreating volume and improving skin quality.38 Adipose tissue harvested with liposuction is processed to yield adipocytes and stromal vascular fraction cells. The stromal vascular fraction is composed of a mixture of adipose stem cells, endothelial cells, vascular smooth muscle cells, and immune cells. The adipocytes provide bulk and improve contour irregularities, and the endothelial and vascular smooth muscle cells assist in blood vessel regeneration (Fig. 1). The adipose stem cells have been shown to modulate the immune system, support angiogenesis, degrade excess extracellular matrix, and undergo adipogenesis. Therefore, fat grafting can theoretically improve skin-related changes associated with scleroderma.

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Immunomodulatory Effects of Fat Grafts

Autologous fat grafts contain adipose stem cells that provide potent antiinflammatory cytokines, which can effectively disrupt the inflammatory response and potentially be beneficial for the treatment of patients with scleroderma. Factors such as indoleamine 2,3-dioxygenase and nitric oxide are secreted by adipose stem cells and induce apoptosis of T and nature killer cells, respectively.39,40 Furthermore, these stem cells have been shown to secrete antiinflammatory cytokines, such as interleukin-10, that inhibit the release of proinflammatory mediators and decrease antigen presentation and phagocytosis.41,42 Together, these findings suggest that one of the mechanisms by which fat grafting may improve outcomes in scleroderma patients is through limiting inflammation.

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Fat Grafts Mitigate Vascular Inflammation and Enhance Angiogenesis and Vasculogenesis

Fat grafting has been shown to improve angiogenesis by providing a rich source of cells and growth factors to support angiogenesis and promote endothelial cell survival. Endothelial cells and vascular smooth muscle cells have been shown to form new blood vessels that provide nutrients to the newly engrafted fat, and the adipose stem cells provide growth factors to the vascular cells in a paracrine fashion.43,44 The synergistic effects of co-implanting adipose stem cells with endothelial cells was demonstrated with rapid formation of functional arterial blood vessels.45 Together, these studies indicate that fat grafting has the potential to promote angiogenesis by providing the cell types to generate new blood vessels.

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Fat Grafting Reduces Fibrosis by Limiting Deposition of Extracellular Matrix Proteins and Increasing Collagenase Activity

Fat grafting reduces the clinical manifestations of fibrosis, likely through the effects of the stem cells found within the processed adipose tissue. Adipose stem cells secrete an abundance of antiinflammatory cytokines that reduce the conversion of fibroblasts to myofibroblasts, thereby lessening the deposition of collagen and other extracellular matrix proteins in the skin and organs. Furthermore, adipose stem cells secrete an abundance of matrix metalloproteinases and collagenase under stressed environments that can degrade the extracellular matrix.46 These findings suggest that the stem cell component of the fat graft has the potential to not only prevent the deposition of collagen and other extracellular matrix proteins but also reverse the underlying fibrosis.

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Fat Grafting Provides Structural Support through Stem Cell Proliferation and Differentiation

No pharmacologic interventions have proven effective to support contour irregularities and lipoatrophy in a poorly vascularized environment, which is common in patients with localized and systemic scleroderma.47 In contrast, fat grafting has allowed for immediate correction of contour irregularities and lipoatrophy, even in poorly vascularized environments.48,49 The engrafted adipocytes provide structural support for the concave irregularities, and the engrafted adipose stem cells have the potential to differentiate into mature adipocytes.48,49 Furthermore, the mixture of cells within the harvested fat secretes factors, as mentioned previously, that soften the thickened and tight skin, which allows for another round of fat grafting. Thus, in many cases, additional rounds of fat grafting are necessary to first soften the skin and provide enough skin laxity to allow for larger volumes of fat injections in the second round.

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FAT GRAFTING STUDIES IN SCLERODERMA PATIENTS

Face

There is increasing interest in using fat grafting to improve the contour irregularities associated with localized scleroderma in the face (Table 1). One of the earliest reports demonstrated improvement in concave irregularities over the frontal scalp in patients diagnosed with linear scleroderma.50 Roh and colleagues corroborated these findings, showing that fat grafting corrected contour irregularities in the forehead with 51 to 75 percent retention even after 1 year.51 Interestingly, treatment of chin irregularities showed less than 25 percent improvement, and correction of nasal deformities demonstrated minimal improvement.51 Since these early studies, several case reports and case series have demonstrated the efficacy of fat grafting of contour irregularities caused by linear scleroderma.51–57 In our experience, contour irregularities in the forehead corrected with fat grafting have shown significant improvement and long-term volume retention (Fig. 2). Other studies have isolated adipose stem cells for the treatment of scleroderma and shown softening of perioral skin along with improvement in the fullness of the malar prominence.58,59

Table 1. - Fat Grafting and Adipose Stem Cell Treatment for Facial Scleroderma
Reference Type of Scleroderma Study Type Level of Evidence Age (yr) No. of Patients Results
Autologous fat grafting
 Roenigk et al., 1988 Linear scleroderma Case series IV 25.0 (range, 17–33) 2 Autologous fat grafting for linear scleroderma over the frontal scalp improved concave irregularities with 70% retention after 1 yr
 Lapiere et al., 2001 Linear scleroderma Case report V 37 1 Fat grafting corrected the concave forehead deformity and volume was maintained after 1 yr
 Roh et al., 2008 Linear scleroderma Case series IV 26.3 (range, 10–55) 20 Fat grafting to improve the contour irregularities found on the forehead showed 51–75% improvement and was maintained for at least 1 yr; for the chin, fat grafting was not as efficacious, with <25% improvement; fat injection into the infraorbital area showed fair correction, but the nose showed the least amount of improvement
 Cho et al., 2010 Linear scleroderma Case report V 26 1 Fat grafting improved linear depression and promoted regrowth of hair on the frontal scalp
 Zanelato et al., 2012 Linear scleroderma Case series IV NR (range, 17–26) 4 Fat grafting improved contour irregularities and volume was maintained after 1 yr
 Consorti et al., 2012 Linear scleroderma Case report V 34 1 Fat grafting provided volumetric restoration of the fronto-orbital region in a patient with linear scleroderma; the improvement remained satisfactory after 2 yr
 Ibler et al., 2015 Linear scleroderma Case series IV NR 3 Fat grafting improved contour irregularities in patients with linear scleroderma; patients received two treatments within 1 yr; the improvement was permanent after 1 yr in all patients
 Barin et al., 2016 Linear scleroderma Case report V 18 1 Fat grafting adequately augmented a depressed scar; at 1 yr, the dermal fat graft remained viable
Adipose stem cell
 Scuderi et al., 2011 Systemic scleroderma Case series IV 34.5 (range, 27–41) 2 Adipose stem cell delivered in a hyaluronic acid solution halted disease progression, improved dyschromia, softened the skin, and reduced sensitivity; patients presented with improved malar prominence
 Karaaltin et al., 2012 Linear scleroderma Case report V 19 1 Adipose stem cells improved contour irregularities at 1 yr postoperatively with no complications
N
R, not reported.

Fig. 2.

Fig. 2.

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Lip and Perioral Region

A limited number of case reports and case series have been performed to investigate the efficacy of autologous fat grafting and adipose stem cells in treating cutaneous manifestations of scleroderma in the lips and perioral region (Table 2). These studies report that autologous fat grafting improved aesthetic and functional outcomes by improving facial expression, mastication, and oral hygiene.60,61 Autologous fat grafting improved interincisal distance, which improved ease of food intake and speech. Patients treated with fat grafts demonstrated improvement in perioral skin sclerosis and sicca syndrome and reduced facial pain.60,61 An additional reported benefit of autologous fat grafting includes the improvement in perioral fullness.62 In our experience, fat grafting reduced deep perioral rhytides and improved skin elasticity in scleroderma patients (Fig. 3). Scuderi and colleagues looked at the efficacy of adipose stem cells on perioral fullness and showed that grafting of adipose stem cells significantly improved fullness with acceptable resorption rates.58 In a prospective study comparing autologous fat grafting to adipose stem cells, there was no significant difference noted between groups, concluding that neither cell treatment was superior.63 However, given the lack of extensive ex vivo processing of autologous fat grafting, fat grafting may be a superior option compared with adipose stem cells.

Table 2. - Fat Grafting and Adipose Stem Cell Treatment of the Perioral Region in Scleroderma Patients
Reference Type of Scleroderma Study Type Level of Evidence Age (yr) No. of Patients Results
Autologous fat grafting
 Ho-Asjoe et al., 1996 Systemic scleroderma Retrospective case report V 41 1 Autologous fat grafting improved perioral aesthetic appearance and mouth opening
 Del Papa et al., 2015 Systemic scleroderma Retrospective case series IV 36.5 (range, 27–53) 20 Autologous fat grafting increased interincisal distance and oral perimeters, induced neovascularization, and restored skin structure 3 mo after treatment
 Sautereau et al., 2016 Systemic scleroderma Retrospective case series IV 53.8 ± 9.6 14 Autologous fat grafting improved maximum mouth opening, perioral skin sclerosis, sicca syndrome, and facial pain as early as 3 wk after treatment
Adipose stem cells
 Scuderi et al., 2011 Systemic scleroderma Retrospective case series IV 34.5 (range, 27–41) 2 Adipose stem cell delivered in a hyaluronic acid solution improved perioral fullness
Autologous fat grafting and adipose stem cells
 Onesti et al., 2016 Systemic scleroderma Prospective clinical trial II 33.2 (20–48) 10 Five patients were treated with fat grafting and five patients were treated with adipose stem cells; both autologous fat grafting and adipose stem cells improved mouth opening and interincisal distance; neither procedure emerged as a superior option

Fig. 3.

Fig. 3.

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Hand

Novel alternative therapeutic strategies are being investigated for patients with scleroderma involving the hands (Table 3). Fat grafting of digital ulcers has been shown to be effective at hastening the healing process, with 80 percent of digital ulcers healed in 8 to 12 weeks.64 In addition, patients have also experienced a significant reduction in hand pain following fat grafting beginning as early as 2 weeks postoperatively.64 In a pilot study, injection of the stromal vascular fraction cells healed all digital ulcers in approximately 4 weeks, with no recurrence.65 Another pilot study showed that the stromal vascular fraction cells were safe, well tolerated, and beneficial in terms of hand pain and edema, Raynaud disease, hand disability, and quality of life.66 The effects appeared long lasting, as there was no recurrence even after 1 year.67 These studies would suggest that both fat grafting and stromal vascular fraction cells from adipose tissue may be useful in treating digital ulcers associated with scleroderma. However, additional clinical studies with larger cohorts are necessary to assess the efficacy of the fat grafts and stromal vascular fraction cells.

Table 3. - Efficacy of Fat Grafting and Adipose Stem Cells for the Treatment of Scleroderma of the Hand
Reference Type of Scleroderma Study Type Level of Evidence Age (yr) No. of Patients Results
Autologous fat grafting
 Bene et al., 2014 Systemic scleroderma Retrospective case series IV 63 (range, 43–76) 9 Autologous fat grafting hastened the healing time of digital ulcer, reduced pain, and reduced the need for pharmacologic therapy; pain improvement was appreciated in 78% of the patients
Stromal vascular fraction cells
 Del Papa et al., 2015 Systemic scleroderma Retrospective case series IV 51.9 (range, 40–66) 15 Stromal vascular fraction cells reduced digital ulcer healing time; treated ulcers healed on average by wk 4; no new digital ulcers appeared in treated patients; pain relief was observed as soon as 1 wk after treatment, with a drastic reduction in analgesic drug use; none of the patients required pain medication 1 mo after treatment; stromal vascular fraction cell were found to improve vascularity
 Granel et al., 2015 Systemic scleroderma Prospective study II 54.5
(range, 34–68)
12 Stromal vascular fraction cells injected into the hands of scleroderma patient was safe; hand fibrosis and pain improved from baseline by 6 mo
 Guillaume-Jugnot et al., 2016 Systemic scleroderma Prospective study II 54.5 ±10.3 12 Stromal vascular fraction treatment improved daily activities, housework, and social activities

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Body

Only one study exists that investigates the efficacy of autologous fat grafting, stromal vascular fraction cells, or adipose stem cells for the treatment of scleroderma that affects the body. Adipose stem cells suspended in hyaluronic acid improved contour irregularities in the upper and lower extremities.58

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STATE OF THE SCIENCE AND FUTURE DIRECTIONS

From a clinical perspective, fat grafting has shown significant promise in improving contour irregularities associated with linear scleroderma, increasing range of motion for digital scleroderma, reducing perioral rhytides associated with systemic scleroderma, and improving skin quality. Although these studies provide an insight into the potential use of fat grafting, the limited number of patients studied prevents defining the indications for fat grafting of scleroderma patients. The optimal time to fat grafting has not been determined (i.e., whether it should be performed early in the disease process before vascular compromise or after contour irregularities become apparent). The optimal volume to inject with each treatment and the number of treatments that a patient should receive remain to be elucidated. Thus, the first step is to perform a retrospective study with a large cohort of scleroderma patients who have been treated with fat grafting. Documentation of the number of treatments, the volume per treatment, and the timing of the treatments from their date of diagnosis or symptom presentation is essential. This study would provide a foundation for which a large, double-blind, prospective study could follow. Long-term follow-up will determine which method prolongs retention. As fat grafting theoretically has the potential to improve the blood supply to the dermis, it has the potential to improve the diffusion of systemic medications to the target site and slow the progression of the disease. Thus, fat grafting may provide benefits early in the disease process and may be used in conjunction with systemic therapies. Nevertheless, additional studies are essential to determine whether fat grafting has a synergistic effect with systemic medications. Large retrospective and prospective studies are essential to investigate the timing of fat grafting, the number of treatments, the volume to inject, the site of injection, the effect on the recipient site, the longevity of the fat grafting, and the potential synergistic effect with systemic medications for scleroderma.

Additional studies are also essential to determine the mechanism by which fat grafting improves outcomes observed clinically. Scleroderma is characterized by a series of pathologic events that includes inflammation, vascular compromise, and ultimately skins fibrosis. It remains to be determined whether fat grafting affects one of these processes or all of these processes and the mechanism by which fat grafting alters the disease progression. Thus, from a microscopic level, it will be essential to characterize the recipient site following fat grafting in scleroderma patients to understand how the growth factors secreted by fat grafts modulate the microenvironment. At the cellular level, the paracrine interaction between the recipient site and the fat grafts remains to be explored. It is possible that the injected fat only provides a reservoir of growth factors that induce angiogenesis or act as chemoattractants to recruit host stem cells or adipocytes to the recipient site. It is also possible that the injected fat grafts engraft into the recipient site and improve contour irregularities. Thus, it will be essential to investigate the composition of the tissue in the recipient site following fat grafting, both in the short term and in the long term. These fundamental studies will provide an understanding of the mechanism by which the donor fat grafts alter the recipient site in scleroderma patients that may then be generalized to other rheumatologic and inflammatory disease processes.

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SUMMARY

Scleroderma is an autoimmune disease that is characterized by inflammation that gradually progresses to fibrosis of the skin and internal organs, resulting in devastating impairments. Limiting the progression of the disease and reversing the fibrosis and atrophy in scleroderma patients is essential. Autologous fat grafting provides a rich source of cells that provide growth factors and structural support, induce angiogenesis, and enhance enzymatic degradation of fibrotic tissue. Each component of the processed adipose tissue has the potential to contribute to the efficacy of fat grafting. Although current studies performed in patients with scleroderma are extremely promising, additional studies are necessary to define the indications of fat grafting of scleroderma patients.

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PATIENT CONSENT

The patient provided written consent for the use of her images.

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REFERENCES

1. Peterson LS, Nelson AM, Su WP. Classification of morphea (localized scleroderma). Mayo Clin Proc. 1995;70:1068–1076.
2. 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. Arthritis Rheum. 2013;65:2737–2747.
3. Kräling BM, Maul GG, Jimenez SA. Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology 1995;63:48–56.
4. Roumm AD, Whiteside TL, Medsger TA Jr, Rodnan GP. Lymphocytes in the skin of patients with progressive systemic sclerosis: Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984;27:645–653.
5. Hasegawa M, Fujimoto M, Kikuchi K, Takehara K. Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J Rheumatol. 1997;24:328–332.
6. Hasegawa M, Sato S, Fujimoto M, Ihn H, Kikuchi K, Takehara K. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J Rheumatol. 1998;25:308–313.
7. Lafyatis R, Farina A. New insights into the mechanisms of innate immune receptor signalling in fibrosis. Open Rheumatol J. 2012;6:72–79.
8. Lafyatis R. Transforming growth factor β: At the centre of systemic sclerosis. Nat Rev Rheumatol. 2014;10:706–719.
9. Varga J, Pasche B. Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol. 2009;5:200–206.
10. Whitfield ML, Finlay DR, Murray JI, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci USA. 2003;100:12319–12324.
11. Akhmetshina A, Dees C, Pileckyte M, et al. Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. FASEB J. 2008;22:2214–2222.
12. Makino K, Makino T, Stawski L, et al. Blockade of PDGF receptors by crenolanib has therapeutic effect in patient fibroblasts and in preclinical models of systemic sclerosis. J Invest Dermatol. 2017;137:1671–1681.
13. Artlett CM. The IL-1 family of cytokines: Do they have a role in scleroderma fibrosis? Immunol Lett. 2018;195:30–37.
14. Maekawa T, Jinnin M, Ohtsuki M, Ihn H. Serum levels of interleukin-1α in patients with systemic sclerosis. J Dermatol. 2013;40:98–101.
15. Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol. 1992;166:255–263.
16. Fleischmajer R, Perlish JS. Capillary alterations in scleroderma. J Am Acad Dermatol. 1980;2:161–170.
17. Kahaleh B. Vascular disease in scleroderma: Mechanisms of vascular injury. Rheum Dis Clin North Am. 2008;34:57–71; vi.
18. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest. 1996;98:785–792.
19. Allanore Y, Batteux F, Avouac J, Assous N, Weill B, Kahan A. Levels of circulating endothelial progenitor cells in systemic sclerosis. Clin Exp Rheumatol. 2007;25:60–66.
20. Fleming JN, Nash RA, McLeod DO, et al. Capillary regeneration in scleroderma: Stem cell therapy reverses phenotype? PLoS One 2008;3:e1452.
21. Bhattacharyya S, Kelley K, Melichian DS, et al. Toll-like receptor 4 signaling augments transforming growth factor-β responses: A novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol. 2013;182:192–205.
22. Takahashi T, Asano Y, Ichimura Y, et al. Amelioration of tissue fibrosis by toll-like receptor 4 knockout in murine models of systemic sclerosis. Arthritis Rheumatol. 2015;67:254–265.
23. Yalçinkaya Y, Çinar S, Artim-Esen B, et al. The relationship between vascular biomarkers and disease characteristics in systemic sclerosis: Elevated MCP-1 is predominantly associated with fibrotic manifestations. Clin Exp Rheumatol. 2016;34(Suppl 100):110–114.
24. LeRoy EC. Increased collagen synthesis by scleroderma skin fibroblasts in vitro: A possible defect in the regulation or activation of the scleroderma fibroblast. J Clin Invest. 1974;54:880–889.
25. Perlish JS, Lemlich G, Fleischmajer R. Identification of collagen fibrils in scleroderma skin. J Invest Dermatol. 1988;90:48–54.
26. Careta MF, Romiti R. Localized scleroderma: Clinical spectrum and therapeutic update. An Bras Dermatol. 2015;90:62–73.
27. Rencic A, Goyal S, Mofid M, Wigley F, Nousari HC. Bullous lesions in scleroderma. Int J Dermatol. 2002;41:335–339.
28. Salem B, Rim BH, Sihem BK, Maher B. Oral manifestations of systemic sclerosis (in French). Pan Afr Med J. 2013;16:114.
29. Bajraktari IH, Kryeziu A, Sherifi F, Bajraktari H, Lahu A, Bajraktari G. Oral manifestations of systemic sclerosis and correlation with anti-topoisomerase I antibodies (SCL-70). Med Arch. 2015;69:153–156.
30. Crincoli V, Fatone L, Fanelli M, et al. Orofacial manifestations and temporomandibular disorders of systemic scleroderma: An observational study. Int J Mol Sci 2016;17:E1189.
31. Avouac J, Walker UA, Hachulla E, et al.; EUSTAR collaborators*; EUSTAR collaborators. Joint and tendon involvement predict disease progression in systemic sclerosis: A EUSTAR prospective study. Ann Rheum Dis. 2016;75:103–109.
32. Mouthon L, Carpentier PH, Lok C, et al.; ECLIPSE Study Investigators. Ischemic digital ulcers affect hand disability and pain in systemic sclerosis. J Rheumatol. 2014;41:1317–1323.
33. Avouac J, Clements PJ, Khanna D, Furst DE, Allanore Y. Articular involvement in systemic sclerosis. Rheumatology (Oxford) 2012;51:1347–1356.
34. Morrisroe KB, Nikpour M, Proudman SM. Musculoskeletal manifestations of systemic sclerosis. Rheum Dis Clin North Am. 2015;41:507–518.
35. Avouac J, Walker U, Tyndall A, et al.; EUSTAR. Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: Results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol. 2010;37:1488–1501.
36. Houtchens J, Martin D, Klinger JR. Diagnosis and management of pulmonary arterial hypertension. Pulm Med. 2011;2011:845864.
37. Sapadin AN, Fleischmajer R. Treatment of scleroderma. Arch Dermatol. 2002;138:99–105.
38. Marten TJ, Elyassnia D. Fat grafting in facial rejuvenation. Clin Plast Surg. 2015;42:219–252.
39. Djouad F, Bouffi C, Ghannam S, Noël D, Jorgensen C. Mesenchymal stem cells: Innovative therapeutic tools for rheumatic diseases. Nat Rev Rheumatol. 2009;5:392–399.
40. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007;110:3499–3506.
41. Iyer SS, Cheng G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol. 2012;32:23–63.
42. Mert T, Kurt AH, Arslan M, Çelik A, Tugtag B, Akkurt A. Anti-inflammatory and anti-nociceptive actions of systemically or locally treated adipose-derived mesenchymal stem cells in experimental inflammatory model. Inflammation 2015;38:1302–1310.
43. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6:389–395.
44. Kapur SK, Katz AJ. Review of the adipose derived stem cell secretome. Biochimie 2013;95:2222–2228.
45. Merfeld-Clauss S, Gollahalli N, March KL, Traktuev DO. Adipose tissue progenitor cells directly interact with endothelial cells to induce vascular network formation. Tissue Eng Part A 2010;16:2953–2966.
46. Wang L, Hu L, Zhou X, et al. Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling. Sci Rep. 2017;7:13321.
47. Chung L, Lin J, Furst DE, Fiorentino D. Systemic and localized scleroderma. Clin Dermatol. 2006;24:374–392.
48. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002;13:4279–4295.
49. Scott MA, Nguyen VT, Levi B, James AW. Current methods of adipogenic differentiation of mesenchymal stem cells. Stem Cells Dev. 2011;20:1793–1804.
50. Roenigk HH Jr, Rubenstein R. Combined scalp reduction and autologous fat implant treatment of localized soft tissue defects. J Dermatol Surg Oncol. 1988;14:67–70.
51. Roh MR, Jung JY, Chung KY. Autologous fat transplantation for depressed linear scleroderma-induced facial atrophic scars. Dermatol Surg. 2008;34:1659–1665.
52. Ibler KS, Gramkow C, Siemssen PA. Autologous fat transplantation for the treatment of linear scleroderma en coup de sabre. Skinmed 2015;13:74–76.
53. Consorti G, Tieghi R, Clauser LC. Frontal linear scleroderma: Long-term result in volumetric restoration of the fronto-orbital area by structural fat grafting. J Craniofac Surg. 2012;23:e263–e265.
54. Lapiere JC, Aasi S, Cook B, Montalvo A. Successful correction of depressed scars of the forehead secondary to trauma and morphea en coup de sabre by en bloc autologous dermal fat graft. Dermatol Surg. 2000;26:793–797.
55. Cho SB, Roh MR, Chung KY. Recovery of scleroderma-induced atrophic alopecia by autologous fat transplantation. Dermatol Surg. 2010;36:2061–2063.
56. Zanelato TP, Marquesini G, Colpas PT, Magalhães RF, Moraes AM. Implantation of autologous fat globules in localized scleroderma and idiopathic lipoatrophy: Report of five patients. An Bras Dermatol. 2013;88(Suppl 1):120–123.
57. Barin EZ, Cinal H, Cakmak MA, Tan O. Treatment of linear scleroderma (en coup de sabre) with dermal fat grafting. J Cutan Med Surg. 2016;20:269–271.
58. Scuderi N, Ceccarelli S, Onesti MG, et al. Human adipose-derived stromal cells for cell-based therapies in the treatment of systemic sclerosis. Cell Transplant. 2013;22:779–795.
59. Karaaltin MV, Akpinar AC, Baghaki S, Akpinar F. Treatment of “en coup de sabre” deformity with adipose-derived regenerative cell-enriched fat graft. J Craniofac Surg. 2012;23:e103–e105.
60. Sautereau N, Daumas A, Truillet R, et al. Efficacy of autologous microfat graft on facial handicap in systemic sclerosis patients. Plast Reconstr Surg Glob Open 2016;4:e660.
61. Ho-Asjoe M, Khan J, Frame JD. Dermal grafting for a patient with scleroderma: Case report. Scand J Plast Reconstr Surg Hand Surg. 1996;30:325–327.
62. Magalon G, Daumas A, Sautereau N, Magalon J, Sabatier F, Granel B. Regenerative approach to scleroderma with fat grafting. Clin Plast Surg. 2015;42:353–364, viii.
63. Onesti MG, Fioramonti P, Carella S, Fino P, Marchese C, Scuderi N. Improvement of mouth functional disability in systemic sclerosis patients over one year in a trial of fat transplantation versus adipose-derived stromal cells. Stem Cells Int. 2016;2016:2416192.
64. Bene MD, Pozzi MR, Rovati L, Mazzola I, Erba G, Bonomi S. Autologous fat grafting for scleroderma-induced digital ulcers: An effective technique in patients with systemic sclerosis. Handchir Mikrochir Plast Chir. 2014;46:242–247.
65. Del Papa N, Di Luca G, Sambataro D, et al. Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis. Cell Transplant. 2015;24:2297–2305.
66. Granel B, Daumas A, Jouve E, et al. Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: An open-label phase I trial. Ann Rheum Dis. 2015;74:2175–2182.
67. Guillaume-Jugnot P, Daumas A, Magalon J, et al. Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up. Rheumatology (Oxford) 2016;55:301–306.
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