Introduction

Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by chronic and often progressive nature, immune system dysfunction, microvasculature damage, and fibrosis of skin and visceral organs [1]. Among the complications affecting the hands, digital ulcers (DUs) are particularly common. Patients experience Raynaud’s phenomenon, which leads to digital ischemia and may result in therapy-resistant ulcerations, pitting scars, or gangrene [2]. In addition to vascular issues, the hands of SSc patients may exhibit sclerodactyly, joint contractures, bony resorption, soft tissue atrophy over distal phalanges, and nail deformities [3], all contributing to pain, severe disability, hand dysfunction,4,5,6 and psychological and aesthetic distress [7]. Treatment for SSc hands has mostly focused on vascular manifestations, particularly digital ulcers, with several medicinal options available [8,9]. However, surgical options for SSc hands are limited. Peripheral periarterial sympathectomy, aimed at improving digital vascularization, and other surgical interventions like microsurgical revascularization or various joint procedures, are designed to address complications [3]. In 2014, Del Bene et al. published pioneering results on treating digital ulcers in SSc patients using autologous fat grafting (AFG) to the fingers [10] a method soon followed by Granel et al. who injected the stromal vascular fraction (SVF) [11]. SVF, first described by Zuk et al. in 2002, is an extraction from adipose tissue containing adipose-derived stem cells (ADSC), various cytokines, and growth factors [12]. Encouraged by the promising findings of Del Bene and Granel our department has treated several SSc patients with this innovative method of autologous stem cell injection into the fingers. This study aims to retrospectively analyze the clinical outcomes of such treatment.

Patients and methods

Patients and data collection

This study presents a retrospective analysis of five systemic sclerosis (SSc) patients treated with stromal vascular fraction (SVF) injections into their fingers between November 2015 and May 2017. The medical files of these patients were reviewed and analyzed retrospectively.

Ethical approval for this project was obtained from the Ethics Committee. Written informed consent was available for four of the five patients. Informed consent could not be obtained from one patient due to missing contact information. For this patient, a waiver was granted by the Ethics Committee.

Outcomes of interest and their relevance

We collected data about the patients’ disease history, patient characteristics and current medication. As part of the 2013 American College of Rheumatology/European League against Rheumatism classification criteria for systemic sclerosis [13], nailfold capillary microscopy was assessed in our patients on a yearly basis. This method detects microvascular damage in SSc patients, which can be divided into three distinct patterns: “early”, “active” and “late” [14,15]. The three patterns correlate with the duration of the disease and its micaroangiopathic evolution during the course of the disease [16]. A semiquantitative Scoring System as suggested by Sulli et al. was used for the analysis [17].

The Cochin Hand function Scale (CHFS), as a measure for overall hand function was noted [18]. The values range from 0 to 90 with higher numbers representing a higher impairment of hand function.

Additionally the modified Rodnan Skin Score (mRSS) [19] was analyzed, a standardized measure of skin thickness that and can be correlated with the disease activity and severity [20]. The score ranges from 0 to 51, measured at 17 body regions, each region can have score 0–3 with higher numbers indicating a more severe skin fibrosis.

The appearance and development of digital ulcers over time was noted. Data about the subjective satisfaction with the treatment was gathered from the clinic’s patient information system.

Statistical analysis

Descriptive statistics included frequencies for categorical variables. Means and ranges were reported for continuously coded variables. R software environment for statistical computing and graphics (version 3.4.3) was used for all statistical analyses.

Surgical technique

All procedures were performed by the same senior surgeon (MC). A preoperative antibiotic prophylaxis with Kefzol 2 g was administered intravenously. Standard liposuction was performed on the thighs or lower abdomen. Fat was suctioned into 10 ml syringes. A total of 5 ml of SVF were then obtained by using the Cytori Celution 800/CRS system (San Diego, California, USA), a fully automated medical device for the standardized extraction and concentration ADSC (Fraser et al., 2014). The SVF Solution was then mixed with 5 ml of ringer’s lactate and distributed into ten 1 ml aliquots. A stab incision was made with a 23 G needle dorso radial and -ulnar on all fingers at PIP-joint level. 0.5 ml were then subcutaneously injected along the course of both neurovascular bundles of each finger, with the tulip 0.7–0.9 mm blunt needle.

Postoperatively the patients were allowed to fully move and put load on the fingers.

Results

Patient characteristics

From November 2015 to May 2017, our clinic treated seven patients suffering from systemic sclerosis with SVF injections into their fingers. Due to missing follow-up data, two patients were excluded upfront. The remaining five patients, all female, had a mean age of 55.6 years (range 38–69 years) at the time of surgery. They had been diagnosed with diffuse cutaneous systemic sclerosis according, and had been treated in the hospital’s Department of Rheumatology beforehand due to their systemic sclerosis. They were referred to the hospital’s Department of Plastic Surgery and Hand Surgery for the SVF injection. The patients were part of EUSTAR (European Scleroderma Trial and Research), an online databank for patients with systemic sclerosis [21,22]. According to the prospective EUSTAR cohort the patients’ data are collected at the Department of Rheumatology on a yearly basis.

Preoperatively, all subjects experienced Raynaud’s phenomenon, with a mean duration of symptoms being 17 years (range 4–30 years). The surgery was indicated due to restrictive skin contractures caused by sclerodactyly in all patients. Additionally, two patients suffered from ongoing digital ulcers at the time of surgery. In one case, the distal phalanx of one finger had previously been amputated due to necrosis that was refractory to treatment. Details on patients’ demographics and related diagnoses are presented in Table 1.

Table 1 Patient characteristics
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At the time of surgery, all subjects were on medication for their disease. The combination of medications taken is summarized in Table 2.

Table 2 Pharmacological therapy at the time of surgery
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Skin and nailfold capillary characteristics

Preoperative nailfold capillaroscopy, conducted at the Department of Rheumatology, was part of the annual scleroderma assessment. Preoperative data for one patient were missing. The other measurements were performed, on average, 5.25 months before surgery (range 2–9 months). All patients exhibited a scleroderma pattern on nailfold capillaroscopy; four had the late type, and one was active on the verge of transitioning to the late type. Postoperatively, the patient on the verge of the late pattern progressed to a manifest late pattern, and one patient shifted from late to active. The remaining three maintained a late pattern. Postoperative measurements were taken, on average, 6.75 months after the intervention (range 3–11 months), excluding the patient with missing preoperative data. We observed a slight increase in the mean semi-quantitative value of irregularly enlarged capillaries, giant capillaries, and hemorrhages; a decrease in capillary loss; and no change in capillary ramifications (Tables 3 and 4).

Table 3 Preoperative nailfold capillaroscopy findings
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Table 4 Postoperative nailfold capillaroscopy findings
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The Cochin Hand Function Scale (CHFS) improved for two patients and worsened for three. The mean preoperative value was 14.0, and the postoperative mean value was 15.4. The preoperative values were collected, on average, 14 months before surgery (range 1–36 months), and the postoperative values were collected 11.4 months after surgery (range 2–23 months) (Table 5).

Table 5 Cochin Hand Function Scale (CHFS) values
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The mean Modified Rodnan Skin Score (mRSS) improved from 14.8 to 11.2 postoperatively. Specifically, the score improved for three patients, worsened for one, and remained unchanged for one (Table 6). Preoperatively, two patients had ulcers: in one, the ulcers healed but two new ones developed; in the other, the ulcers also healed, although this patient had received a Botox infiltration between the operation and the reported healing. The patient whose mRSS score worsened developed new pitting scars and sclerodactyly post-surgery, which had not been previously reported. This patient, along with two others, did not report any significant change or improvement in hand function following the intervention. The remaining two subjects experienced a slight improvement in the softness of finger movement.

Table 6 Modified Rodnan skin score (mRSS) values
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Discussion

Systemic sclerosis poses a significant challenge for both doctors and patients [1,21]. The hand disabilities caused by the disease represent a therapeutic challenge, as all available treatment options offer only limited relief. Encouraged by the promising results of a previous uncontrolled clinical trial [11], we decided to treat systemic sclerosis patients suffering from digital ulcers refractory to medical treatment, or severely impaired hand function due to sclerodactyly, with SVF injections. Our study yielded several noteworthy findings.

Firstly, we observed no clear improvement in nailfold capillaroscopic measurements post-intervention. Nailfold capillary microscopy serves as a measure for microangiopathies. The semiquantitative scores for “irregularly enlarged capillaries,” “giant capillaries,” and “hemorrhages” increased in our patient cohort, suggesting a deterioration. According to Cutolo et al., these parameters are predominantly present in the early stages of the disease [22]. In contrast, a ‘late pattern’ of the disease is characterized by an almost absent presence of giant capillaries and microhemorrhages, with “loss of capillaries” and “capillary ramifications” being more prominent. The patient with the shortest disease duration since diagnosis (4 years) showed a shift from an ‘active to late’ pattern preoperatively to ‘late’ postoperatively. One patient transitioned from a ‘late’ to an ‘active’ pattern postoperatively. These findings are challenging to interpret, especially since other studies reported a decrease in all capillaroscopic findings after SVF treatment [11,23].

Given the proposed antifibrotic properties of ADSC, we had anticipated an improvement in skin quality and consequently an enhancement of hand function after the treatment. However, the mean CHFS score in our cohort slightly increased, indicating a decrease in patient-reported function. This contrasts with Granel et al. [11]. , who reported a 50% improvement in CHFS at 2 and 6 months postoperatively, and Park et al. [24], who observed a persistent CHFS increase up to the last follow-up at 24 weeks post-surgery. The latest results of a placebo-controlled study (Daumas et al., 2021) following Granel et al. (2015) showed a mean CHFS decrease of 7.9 points at 6 months postoperatively in the treatment group, but an even greater decrease of 10.8 in the control group, which was injected with Ringer’s lactate solution only [25]. Baseline conditions and study designs differ substantially among these studies, and so far, no clear effect of ADSC treatment on the CHFS score has been demonstrated.

Skin thickening, a hallmark symptom of systemic sclerosis, decreased post-intervention in our patients. Similar trends were observed by Park et al. [24] with a decrease from 7.5 preoperatively to 3 at 24 weeks postoperatively, and by Granel et al. [11] with a decrease from 13.9 to 11.5 at 6 months postoperatively. A decrease in skin thickness can impact digital mobility and, therefore, contribute to improved usability of the affected hand.

Regarding digital ulcers, we found no explicit benefit from the treatment for better or faster healing of the ulcers. In one patient whose ulcers healed, two new ones developed, and in another, healing occurred only after additional Botox infiltration. Although several authors have reported a reduction in the number of digital ulcers after ADSC treatment [10,26,27,28,29], we could not validate these results in our patients.

This study has several limitations. It has a small study size and larger study sizes might be needed to draw more general conclusions. It is crucial however to acknowledge that, in the realm of rare diseases, conducting large-scale studies poses significant logistical and ethical challenges, often making small-scale studies not only practical but also immensely valuable. Moreover, small study sizes, while limiting in statistical power, offer the opportunity for in-depth, detailed case analysis. This can be particularly advantageous in understanding the nuanced presentations of rare diseases like systemic scleorosis, which might be lost in larger studies. Being a retrospective study, our study may be prone to observer bias. Also, functional scores, such as range of motion, were not assessed but may hold less importance for this specific patient group. For greater impact, our conclusions should be reassessed by prospective data for greater impact.

Conclusions

Despite the limitations mentioned above, this study suggests that previously published promising results should be considered with caution. While studies have confirmed the safety and feasibility of this treatment modality, further randomized controlled trials with large, homogeneous populations are necessary to establish clear indications for patients who may benefit from this treatment.