A systematic review of therapeutic procedures for the treatment of morphea and systemic sclerosis

Considering the challenges involved in managing morphea and systemic sclerosis—especially the risks of disease reactivation and inflammation following treatment—and the limited evidence on the effectiveness and safety of treatment methods like energy-based devices and intralesional injections, it is essential to conduct a systematic review to compile and critically evaluate the available data comprehensively. This review aims to evaluate the effectiveness and safety of energy-based devices and intralesional injections in managing morphea and systemic sclerosis, to provide critical evidence that informs clinical decision-making and ultimately enhances patients’ quality of life. This study was conducted as a systematic review following established guidelines and checklists for such reviews. The PRISMA flow diagram was employed to illustrate the identification, screening, eligibility, and inclusion of studies. Comprehensive searches were performed from different scientific databases, including PubMed, Scopus, Web of Science, and Embase, to identify all relevant studies evaluating the effectiveness and safety of energy-based devices and intralesional injections in treating morphea and systemic sclerosis. We managed the retrieved records using EndNote reference management software. After a thorough screening process, we extracted relevant data based on predefined study variables and then analyzed it. This study reviewed 28 articles published between 2010 and 2025. Of these, 17 articles (60.7%) were clinical trials, 4 (14.3%) were retrospective studies, 4 (14.3%) were cohort studies, 2 (7.1%) were cross-sectional studies, and 1 (3.6%) was a case series, encompassing a total of 732 patients. Among the patients, 114 (15.6%) were men and 618 (84.4%) were women, ranging from 6 to 70 years. Of the studies reviewed, 14 articles (50%) focused on morphea, 12 articles (42.9%) on systemic sclerosis, and 2 articles (7.1%) examined both conditions. A total of 15 studies (53.6%) evaluated the efficacy and safety of energy-based devices, with UVA-1 phototherapy being the most frequently studied modality, appearing in 9 articles (60%). Other energy-based treatments included ablative fractional CO₂ laser (2 studies, 13.3%), a comparison of UVA-1 and CO₂ laser (1 study, 6.7%), Water-Filtered Infrared A plus Visible Light (1 study, 6.7%), LEDs emitting at 850 nm (infrared), 660 nm (red), and 405 nm (violet) (1 study, 6.7%), and Fibroblast Activation Protein Targeted Photodynamic Therapy (1 study, 6.7%). The remaining 13 studies (46.4%) investigated intralesional injections, with stromal vascular fraction (SVF) gel (2 studies, 15.4%), injecting fat micrografts along with fat-derived SVF (1 study, 7.7%), Botulinum toxin (BTX) (4 studies, 30.8%), injection of ozone/oxygen (1 study, 7.7%), hyaluronic acid filler (2 studies, 15.4%), PRP combined with autologous SVF (1 study, 7.7%), Hydrodissection + injection of 80 mg of triamcinolone acetonide (1 study, 7.7%), and autologous fat grafting (1 study, 7.7%) being the most common intralesional treatments. Follow-up durations varied from 5 days to 37 months. Positive therapeutic outcomes were reported in two studies involving energy-based devices and in all but one study involving intralesional injections. Furthermore, none of the studies reported any life-threatening adverse events from these treatments. The promising therapeutic efficacy and lack of severe adverse effects reported in the literature regarding energy-based devices and intralesional injections for managing morphea and systemic sclerosis suggest a favorable outlook for their clinical use, particularly in patients with refractory forms of the disease. Further clinical trials and genetic research in this field could strengthen the methodological rigor of future studies, support the development of innovative treatment strategies, and help identify patients most likely to benefit from specific therapies.

Supplementary information

The online version contains supplementary material available at 10.1007/s10103-026-04799-3.

Key messages

What is already known about this topic?

• Morphea primarily affects dermis and subcutaneous tissue but impacts health-related quality of life (HRQoL) in 20–50% of adults and children.

• Patients with systemic sclerosis frequently experience psychiatric comorbidities such as anxiety, depression, obsessive thoughts, and guilt, which further worsen morbidity and survival.

What does this study add?

• UVA-1 phototherapy in morphea led to a 57% reduction in skin thickness and 60% decrease in LoSCAT and DLQI scores, showing significant antifibrotic activity.

• 51% of morphea patients responded positively to UVA-1 phototherapy across 15 sessions, supporting its role as a viable option for selected dermatoses.

• Recurrence after UVA-1 therapy in morphea was high, with 44.5% at 2 years and 48.4% at 3 years, suggesting limited durability of phototherapy outcomes.

• Patients receiving PUVA photochemotherapy showed significantly greater reductions in sTNFαR1 concentrations and improved clinical outcomes compared to penicillin-treated patients.

• Fractional CO₂ laser therapy improved skin flexibility, reduced induration, and enhanced cosmetic outcomes in morphea lesions.

• Combination therapy using fractional CO₂ laser with UVA-1 phototherapy showed superior clinical improvement compared to monotherapy.

Supplementary information

The online version contains supplementary material available at 10.1007/s10103-026-04799-3.

Introduction

Systemic sclerosis (SSc) is an immune-mediated rheumatic disease [1, 2] characterized by chronic autoimmune-driven fibrosis of the skin and multiple internal organs. The process starts with damage to the endothelium, which then triggers a series of inflammatory and fibrotic responses [3]. Among the most frequent and often initial manifestations of systemic sclerosis is vascular dysfunction, exemplified by Raynaud’s phenomenon [4]. Furthermore, ocular complications represent another vascular-related aspect of the disease, with ocular manifestations potentially indicating systemic microvascular abnormalities involving the eye’s microcirculation [5]. The occurrence of skin thickening on the fingers, particularly near the metacarpophalangeal joints, is sufficient for diagnosing SSc [6]. The disease’s impact varies depending on its subtype, severity, and the specific anatomical location of lesions, potentially involving various connective tissues, including adipose tissue, muscle, joints, and bone [7].

Morphea is a chronic inflammatory skin disorder of connective tissue presenting in various clinical forms and affecting individuals across all age groups, from children to adults [8]. While morphea predominantly targets the dermis and subcutaneous tissue, systemic sclerosis generally encompasses skin and multiple internal organs [9]. Skin manifestations are the initial and most noticeable indicators of SSc and its related conditions, underscoring the critical role of dermatologists in identifying these symptoms for precise diagnosis and effective management [10]. Research reveals that morphea adversely affects health-related quality of life (HRQoL) in 20% to 50% of both adults and children [11].

Procedural therapies, particularly energy-based devices including lasers, light-based modalities, and phototherapy, as well as injection-based approaches such as regenerative medicine, play an important role in the management of various dermatologic conditions [12, 13]. In this systematic review, we discuss the role of procedural interventions in the treatment of different forms of SSc and morphea.

Materials and methods

Search strategy and databases

This study was conducted as a systematic review after receiving approval from the Ethics Committee of Iran University of Medical Sciences. In the initial phase, we clearly and specifically defined the study objectives. The principal purpose was to examine the efficacy and safety of energy-based devices and intralesional injections for treating morphea and SSc. Following international guidelines (PRISMA), we developed a comprehensive systematic review protocol that detailed the article search procedures, inclusion and exclusion criteria, and methods for data analysis. To systematically search for articles, reputable databases such as PubMed, Scopus, Web of Science, and Embase were thoroughly examined. We formulated a set of relevant keywords and combined them using logical operators (AND, OR) to maximize the retrieval of pertinent studies. The specific search strategy developed for each database is detailed in Table S1. The search included all publications available until March 15, 2025 (see Fig. 1). Additionally, we reviewed reference lists of related articles and earlier reviews to identify more studies that met the eligibility criteria.

Fig. 1.

The PRISMA flowchart includes the stages of review and entry of articles into the study

The inclusion and exclusion criteria

The PICO in this study involved patients with morphea and SSc (P), interventions involving treatment using energy-based devices and intralesional injections (I), comparisons with conventional or traditional treatments for morphea and SSc (C), and outcomes focused on assessing the effectiveness and safety of the therapy in promoting wound healing, reducing inflammation, and improving quality of life (O). The inclusion criteria consisted of studies published between 2010 and 2025 that assessed the effectiveness and safety of energy-based devices and intralesional injections in patients with morphea and SSc, with eligible study designs including clinical trials, cohort studies, and case-control studies. We excluded studies with insufficient data or incomplete results, were systematic reviews or case reports, or involved non-human subjects such as animal models.

Study selection and data extraction

The screening process was performed by two independent researchers. Initially, they reviewed the titles and abstracts, excluding any irrelevant studies. Then, we examined the full texts of the remaining articles and selected eligible studies based on the predefined inclusion and exclusion criteria. Next, independent researchers carried out data extraction in two stages, each independently entering information into a standardized extraction form. The researchers then compared the extracted data and resolved any discrepancies through discussion. To ensure the validity and reliability of the extracted data, a third researcher conducted a review. Additionally, they verified the data against the original articles for consistency. Finally, the team recorded and stored all collected data electronically. A standardized form was developed for data extraction, capturing the following information: study characteristics (including study design, year of publication, and first author), features of the study population (such as number of participants, age, gender, and prior treatments), type of therapeutic intervention (energy-based devices and intralesional injections), and primary outcomes (treatment efficacy, adverse events, and indicators of disease improvement).

Assessing risk of bias and quality of the articles

The Cochrane Risk of Bias Tool for Randomized Trials Version 2 (RoB 2) was employed to evaluate the quality of clinical trial studies (see Figure S1). At this time, the Newcastle–Ottawa Scale (NOS) was utilized to assess the quality of observational studies (see Figure S2). For case series studies, we assessed study quality using the NIH Quality Assessment Tool, as illustrated in Figure S3.

Data analysis and ethical considerations

This review presents the data through descriptive analyses. We organized the results in tables, categorizing them by study characteristics such as intervention type, patient population, and outcomes. The analyses involved summarizing findings and identifying trends, inconsistencies, and research gaps. We conducted all stages of the study with transparency, scientific rigor, and adherence to ethical standards. We reported information from the articles based on the variables under investigation. We used Microsoft Excel to organize and analyze the data. We describe qualitative data using percentages and frequencies, while we report quantitative data as mean ± standard deviation (SD).

Ethical considerations included selecting articles free of conflicts of interest and bias, respecting the confidentiality of information from the articles, and properly referencing them at all stages of the study.

Results

An initial search, using topic-specific keywords within the defined timeframe, yielded 745 articles from various databases. We deleted 226 duplicate articles by entering their titles into EndNote software. A subsequent review of titles and abstracts resulted in excluding 408 articles for irrelevance. Among the remaining 111 articles, 1 could not be retrieved. During the full-text review of the remaining 110 articles, we excluded 30 for mismatching the disease type, 11 for being reviews, 41 for mismatching the studied treatment method,. Ultimately, we included 28 articles in the final review (Fig. 1).

The study analyzed 28 articles published between 2010 and 2025 [14–41]. Among these, 17 (60.7%) were clinical trials, 4 (14.3%) were retrospective studies, 4 (14.3%) were cohort studies, 2 (7.1%) were cross-sectional studies, and 1 (3.6%) was a case series, including a total of 732 patients. The patient population consisted of 114 men (15.6%) and 618 women (84.4%), with ages ranging from 6 to 70 years. Of the reviewed studies, 14 (50%) focused on morphea, 12 (42.9%) on systemic sclerosis, and 2 (7.1%) examined both conditions.

A total of 15 studies (53.6%) assessed the effectiveness and safety of energy-based devices, with UVA-1 phototherapy being the most commonly investigated treatment, appearing in 9 studies (60%). Other energy-based modalities included ablative fractional CO₂ laser (2 studies, 13.3%), a comparison of UVA-1 and CO₂ laser (1 study, 6.7%), Water-Filtered Infrared A plus Visible Light (1 study, 6.7%), LEDs emitting at 850 nm (infrared), 660 nm (red), and 405 nm (violet) (1 study, 6.7%), and Fibroblast Activation Protein Targeted Photodynamic Therapy (1 study, 6.7%). The remaining 13 studies (46.4%) investigated intralesional injections, with stromal vascular fraction (SVF) gel (2 studies, 15.4%), fat micrografts combined with fat-derived SVF (1 study, 7.7%), Botulinum toxin (BTX) (4 studies, 30.8%), ozone/oxygen injections (1 study, 7.7%), hyaluronic acid fillers (2 studies, 15.4%), PRP combined with autologous SVF (1 study, 7.7%), Hydrodissection with an 80 mg injection of triamcinolone acetonide (1 study, 7.7%), and autologous fat grafting (1 study, 7.7%) being the most frequently used intralesional treatments.

Follow-up durations ranged from 5 days to 37 months. Positive therapeutic outcomes were reported in two studies involving energy-based devices and in all but one study involving intralesional injections. Additionally, no life-threatening adverse events were reported in any of the studies.

All but two energy-based devices [17, 20] and all but one intralesional injection [30] were associated with positive treatment efficacy in managing morphea and SSc. In the cross-sectional study by Chia et al. (2020) [17], UV-A1 radiotherapy showed only a partial response and required a more extended treatment duration. Similarly, the cohort study by Vasquez et al. (2014) [20] reported a high relapse rate following UV-A1 radiotherapy. Additionally, in a clinical trial by Bello et al. (2017) [30], patients with SSc showed greater clinical improvement following BTX-A injection than those with localized forms of the disease. Importantly, none of the studies reported any life-threatening adverse effects related to these treatment modalities (Table 1).

Table 1.

Data collected from the articles reviewed in the study

First Author	Publication year	Study type	Sample size	Age (Mean)	Gender	Type of disease	Treatment	F/U	Efficacy	Safety
Energy-based devices
Tognetti (15)	2021	Clinical trial	16	55.4	6 men, 10 women	Morphea	Medium-dose UVA-1 phototherapy	3 months	Following the final phototherapy session, skin thickness, LoSCAT scores, and DLQI gradually decreased by 57% and 60%, respectively. Molecular gene analysis (RT-PCR) showed that UVA-1 phototherapy has multiple effects, including activating specific antifibrotic pathways and reducing certain profibrotic pathways, as evidenced by a significant overexpression of IL-1ß. Additionally, collagen synthesis was stabilized.	-
Dorst (16)	2021	Clinical trial	25	Not specified	Not specified	Systemic sclerosis	Fibroblast Activation Protein Targeted Photodynamic Therapy	5 days	The treatment caused dose-dependent, antibody-mediated cytotoxicity in primary skin fibroblasts when they were exposed to light. In contrast, fibroblasts that were not exposed to light or incubated with a nonspecific photosensitizing antibody construct did not show this effect. The intervention entirely inhibited the contraction of collagen grafts implanted with primary fibroblasts. Remarkably, even a very low antibody concentration (0.4 nM) suppressed fibroblast contraction from two of the three donors tested. This investigation provides the first evidence demonstrating the potential of this treatment to modulate cutaneous manifestations of systemic sclerosis.	-
Chia (17)	2020	Retrospective cohort	17	44.7	-	Systemic sclerosis	UV-A1 phototherapy	30 sessions	After 10 and 20 sessions of UVA1 phototherapy, only 11.8% and 10% of patients, respectively, showed a good response. However, this response rate increased to 40% after 30 sessions. Ultraviolet A1 phototherapy induces a partial response in patients with SSc and generally requires more extended treatment duration to achieve better outcomes.	The most common side effects experienced in the study were pruritus and erythema.
Zbiciak-Nylec (14)	2020	Cohort	41	48.8	6 men, 35 women	Morphea	PUVA phototherapy	6 weeks	The difference in particle levels determined in patients receiving photochemotherapy (mean: 106.25 ng/ml) was greater than in the group receiving penicillin (mean: 81.50 ng/ml). Patients treated with PUVA sessions exhibited a greater decrease in sTNFαR1 concentrations and improved clinical status following the completion of treatment.	-
Hughes (18)	2019	Clinical trial	8	48.5	1 man, seven women	Systemic sclerosis	LEDs emitting at 850 nm (infrared), 660 nm (red), and 405 nm (violet).	8 weeks	VAS scores improved significantly during the study, with mean changes of −7.1 and − 5.2, respectively (P < 0.001). The wound perfusion also increased considerably after irradiation. Overall, radiation therapy for digital ulcers was safe, feasible, and well tolerated.	No side effects
Attili (19)	2017	Cross sectional	37	44	-	Morphea	phototherapywith UV-A1	15 sessions	Phototherapy demonstrated positive therapeutic effects in 19 (51%) of 37 patients with morphea. These results suggest that ultraviolet A1 phototherapy may be considered a treatment option for selected dermatoses. However, the long-term risk of malignancy associated with this therapy remains unknown.	Overall, patients tolerated the treatment well, and no one withdrew from the study due to side effects related to the treatment.
Vasquez (20)	2014	Cohort	37	35.9	10 men, 27 women	Morphea	UV-A1 phototherapy: 340–400 nm	37 months	46% of patients experienced a relapse of active morphea lesions following successful UVA1 phototherapy. The recurrence rates at two and three years post-final UVA1 treatment were 44.5% and 48.4%, respectively. The sole factor significantly correlated with recurrence was the duration of morphea before initiating UVA1 therapy (P = 0.02).	-
Felbert (21)	2011	Case series	10	Not specified	one man, nine women	Systemic sclerosis	Water-Filtered Infrared A plus Visible Light	-	In 7 of the 10 patients, treatment resulted in significant improvement. Of the remaining patients, 1 showed a reduction in sclerosis and disease activity, which worsened after discontinuation of therapy. In two patients who had not previously responded to UVA1 treatment, this therapy produced a slight reduction in skin sclerosis, although disease activity remained. Overall, wIRA(+ VIS) appears to be efficient in treating SSc.	-
Malewska-Woźniak (22)	2022	Retrospective study	31	Not specified	Not specified	Morphea	PUVA and UVA1 Phototherapy	Not specified	Both treatments resulted in significant clinical improvement	No serious side effects reported
Su (23)	2011	Retrospective study	35	Not specified	Not specified	Morphea	Medium-Dose UVA1 Phototherapy	Not specified	82.85% of patients showed significant clinical improvement, with reduction in skin thickness	No side effects reported
Andres (24)	2010	Retrospective and Prospective study	30	Not specified	Not specified	Morphea	Medium-Dose UVA1 Phototherapy	6 months to 3 years	82% improvement in symptoms in retrospective group, 77% increase in skin elasticity and 13% reduction in skin thickness in prospective group	No serious side effects reported
Connolly (25)	2015	Retrospective study	83	Not specified	44 females, 39 males	Systemic Sclerosis	UVA1 Phototherapy	Not specified	High-dose UVA1 was effective for systemic sclerosis, GVHD, and NSF; medium- and high-dose regimens showed the best response	Adverse effects were rare, including erythema and fatigue in some patients
El-Shahawy (26)	2025	Comparative cross-sectional study	30	Not specified	Not specified	Morphea	Group1: Fractional CO₂ laser (10,600 nm), Group 2: Microneedling.	1-month evaluation after the last treatment session	Significant reduction in clinical score (LoSCAT) in both groups; improvement in histopathological scores.	High patient satisfaction reported; no serious side effects noted.
Guo Q (27)	2022	Randomized controlled clinical trial	22	Not specified	Not specified	Morphea	Group AFL (ablative fractional laser), Group AFL + MTX (ablative fractional laser-assisted delivery of methotrexate).	Four-month treatment period; detailed follow-up data after treatment is not fully clear.	Both groups were effective; AFL + MTX had better outcomes in clinical appearance (p = 0.042) and dermal thickness (p = 0.016).	No serious side effects reported.
Shalaby (28)	2016	Randomized controlled clinical trial	17	Not specified	Not specified	Morphea	Lesion 1: UVA-1, Lesion 2 (same patient): fractional CO₂ laser (10,600 nm.	Clinical, histological, and immunohistochemical evaluation (TGF-β1, MMP1); detailed post-treatment follow-up time is unclear.	Fractional CO₂ laser was significantly better than low-dose UVA-1 in clinical score (p = 0.001), collagen homogeneity score (p = 0.012), and patient satisfaction (p = 0.001).	No specific side effects noted; the treatment method was considered safe and effective.
Intralesional injections
Liu (29)	2024	Non-randomized clinical trial	44	26.2	8 men, 36 women	Morphea	SVF gel at 1 and 2 months after sequential fat grafting	12 months	The mean (SD) mLoSSI scores at 12 months showed a decrease of 1.6 (1.50), while the mean (SD) LoSDI scores decreased by 4.3 (1.34), indicating that patients receiving stromal vascular fraction (SVF) gel experienced considerable increase in morphea skin lesions; however, disease activity did not significantly decline. Histological analysis demonstrated enhanced skin regeneration and reduced skin sclerosis. The results from this trial confirm that sequential grafting of fresh fat and cryopreserved SVF gel is safe, with histological and transcriptomic evidence further supporting its efficacy in treating morphea.	No significant side effects noted.
Iglesias (30)	2023	Clinical trial	20	55.4	1 man, 19 women	Systemic sclerosis	Injecting fat micrografts along with fat-derived SVF into patients’ hands	168 days	After the study, statistically significant reductions in pain intensity recorded. The injection of fat micrografts combined with fat-derived stromal vascular fraction (SVF) represents a consistent and safe procedure. This approach employed in conjunction with conventional medical therapies to successfully alleviate pain and treat finger ulcers in individuals with systemic sclerosis.	No side effects observed.
Shenavandeh (31)	2022	Clinical trial	26	39.5	6 men, 20 women	Systemic sclerosis	In the first group, a dermatologist administered 20 units BTX-A injections at the base of each affected finger. In the second group, patients received daily injections of either 20 micrograms of iloprost or 60 micrograms of alprostadil.	1 month	Wound healing occurred in 95.5% of patients treated with BTX-A and 90.5% of those in the prostaglandin group. Both groups experienced a significant reduction in pain. Capillaroscopy revealed a notable decrease in microbleeds in both groups. Moreover, the BTX-A group experienced significantly reduced outpatient treatment costs and gained considerable time savings.	In one patient (affecting 4.5% of fingers), a localized finger infection developed following BTX-A injection, which resolved with oral and topical antibiotic treatment no notable complications were reported in the second group.
Elawamy (32)	2020	Randomized clinical trial	50	38.6	-	Systemic sclerosis	Group O (injection of ozone/oxygen 25 µg/ml in 20 ml) and Group M (methylprednisolone acetate 40 mg plus 40 mg lidocaine in 20 ml)	6 months	Pain intensity, as measured by VAS scores, was significantly reduced in Group M at the 1-week mark, whereas Group O exhibited substantially lower VAS scores at 3 and 6 months. Moreover, both groups showed a marked decline in VAS scores throughout the study period relative to their initial baseline. The Carpal Tunnel Syndrome Hand Function Scale (CHFS) score improved in the ozone group at six months. Additionally, distal motor latency significantly shortened in the ozone group at 3- and 6-month evaluations.	-
Lautenbach (33)	2020	Clinical trial	7	53.1	One man, six women	Systemic sclerosis	BTX-A injected at an average dose of 90 units in each hand.	24 months	Of the 31 wounds in all patients, 77% (n = 24) healed. The median time to wound closure was 8 weeks, with a total healing duration of 8 months. Improvements in blood flow and pain reported in 60% of cases. BTX-A injections may benefit selected patients with systemic sclerosis who have chronic, refractory wounds; however, a well-powered prospective study is needed to confirm these findings.	-
Pirrello (34)	2019	Clinical trial	10	Not specified	Ten women	Systemic sclerosis	injections of hyaluronic acid filler and platelet-rich plasma.	24 months	Patients experienced positive outcomes following the initial injection, with improvements sustained for up to two years. Notably, eight patients (80%) demonstrated increased mouth opening and enhanced upper lip thickness at the 1-month follow-up, and these benefits were maintained through the 24-month assessment. Additionally, all patients showed increases in the distance between the upper and lower incisors, inter-commissural distance, and lower lip thickness at 1 month, which were sustained at 24 months. Skin elasticity also increased 1 month after treatment ended. This study suggests that hyaluronic acid filler injections combined with platelet-rich plasma are an effective treatment alternative for patients with SSc, significantly improving both functional outcomes and quality of life.	-
Virzi (35)	2017	Clinical trial	6	Not specified	Two men, four women	Systemic sclerosis	PRP combined with autologous SVF	3 months	The combined administration of platelet-rich plasma (PRP) and stromal vascular fraction (SVF) improved buccal contour, increased skin elasticity, and enhanced vascularization in all patients. This novel regenerative approach holds promise as a therapeutic option for chronic connective tissue disorders, including systemic sclerosis.	-
Motegi (36)	2017	Clinical trial	45	60.7	4 men, 41 women	Systemic sclerosis	Treatment groups using 250, 1000, or 2000 international units (U) of botulinum toxin type B (BTX-B) injections in the hand.	16 weeks	Four weeks post-injection, Visual Analog Scale (VAS) scores for pain and numbness, along with Raynaud’s phenomenon scores, were significantly reduced in the groups treated with 1000 and 2000 units of BTX-B compared to both the control group and the group receiving 250 units of BTX-B. These therapeutic benefits sustained for up to 16 weeks following a single injection. Furthermore, the number of ulcers was markedly lower in the 1000 and 2000-unit BTX-B groups relative to the control group.	Among the reported adverse events, transient muscle weakness was observed in one patient from the 2000-unit BTX-B group, lasting from 5 days up to 3 weeks post-injection. No systemic or local adverse effects, including anaphylactic reactions, reduced muscle strength, dysphagia, xerostomia, or abnormal liver function, were noted in any of the patients. Although patients reported pain at the injection site, this discomfort resolved within a few hours.
Bello (37)	2017	Randomized clinical trial	40	51.9	9 men, 31 women	25 cases of morphea, and 15 cases of SSc	Btx-A (50 units in 2.5 ml)	4 months	From baseline to the 1-month follow-up, the Btx-A group exhibited a significantly greater reduction in mean blood flow compared to the placebo group, a result primarily influenced by patients with SSc. By the 4-month assessment, however, the differences in blood flow between the groups were no longer statistically significant. These outcomes do not support recommending Btx-A for all individuals with SSc. Although some secondary clinical endpoints indicated favorable effects, their practical clinical importance remains uncertain.	Two participants (5%) experienced weakness of the intrinsic muscles of the hand after receiving study injections. Both cases were treated with Btx-A, and none were seen in the hands treated with placebo.
Granel (38)	2014	Clinical trial	12	54.5	12 women	Systemic sclerosis	Autologous SVF	6 months	Notable enhancements detected in hand dysfunction and pain, Raynaud’s phenomenon, digital swelling, and overall quality of life. This study confirms the safety of autologous stromal vascular fraction (SVF) cell infusion into the hands of patients with systemic sclerosis (SSc). Preliminary assessments at 6 months indicate its potential effectiveness warrants validation through a larger, randomized, placebo-controlled trial.	No serious adverse events occurred during the procedure or throughout the follow-up period. Four minor adverse events documented, all resolved spontaneously without intervention.
DeLea (39)	2011	Clinical trial	12	42.7	2 men, 10 women	Systemic sclerosis	Hydrodissection + injection of 80 mg of triamcinolone acetonide	12 months	Hydrodissection combined with corticosteroid injection resulted in a substantial 67% reduction in pain scores among patients with SSc. This therapeutic approach effectively alleviates pain and vasomotor symptoms in SSc affecting the hands. The underlying mechanism involves the mechanical release of constricted arteries, nerves, and tendons through hydro dissection, coupled with the anti-inflammatory effects of corticosteroids that mitigate vasospasm.	No complications observed.
Owczarczyk-Saczonek (40)	2020	Case series	3	34.3	3 women	Morphea	Hyaluronic acid (HA) injections (Juvéderm Voluma or Volux). In one case, HA injections were combined with fractional ablative CO2 laser (FAL) therapy.	6 months to 3 years	The Localized Scleroderma Damage Index (LoSDI) score decreased from 7 to 3 on average, reflecting a 57% reduction in skin damage. Significant aesthetic improvement was observed, with no disease progression during the follow-up period. High patient satisfaction with the cosmetic outcomes.	The procedure was well-tolerated with minimal adverse effects. No disease relapse or exacerbation observed during the follow-up period. The combination of HA injections with FAL therapy also showed a safe profile with no significant complications.
Baserga (41)	2020	Nonrandomized controlled trial	18	33	11 women, 7 men	Morphea	autologous fat grafting (lipofilling),	12 months	The RMS (Root Mean Square) values for the middle facial third significantly improved after treatment, with a decrease from > 1.00 mm to < 0.80 mm. At T2, all three facial thirds (upper, middle, and lower) showed significant improvement, with RMS values aligning with those of healthy controls. Z-scores for all facial thirds improved significantly, indicating a substantial reduction in facial asymmetry.	No serious adverse events (AEs) No serious adverse events (AEs), including infection, necrosis, or embolization, were reported. Minor AEs such as pain, skin irregularities, and paresthesia were observed but resolved within the follow-up period. were recorded. Minor AEs included pain, skin irregularities, and paresthesia, which resolved within the follow-up period. No significant complications such as infection or necrosis were observed throughout the treatment course.

Energy-based devices

A total of 15 studies (53.6%) assessed the effectiveness and safety of energy-based devices, with UVA-1 phototherapy being the most commonly investigated treatment, appearing in 9 studies (60%). Other energy-based modalities included ablative fractional CO₂ laser (2 studies, 13.3%), a comparison of UVA-1 and CO₂ laser (1 study, 6.7%), Water-Filtered Infrared A plus Visible Light (1 study, 6.7%), LEDs emitting at 850 nm (infrared), 660 nm (red), and 405 nm (violet) (1 study, 6.7%), and Fibroblast Activation Protein Targeted Photodynamic Therapy (1 study, 6.7%).

UV-A1 phototherapy

Morphea

A 2021 clinical trial by Tognetti et al. [15] evaluated the effectiveness of moderate-dose UVA-1 phototherapy in 16 patients with morphea. The study observed a continuous reduction in skin thickness and in LoSCAT and DLQI scores from the end of phototherapy through the 6- and 9-month follow-up assessments, with decreases of 57% and 60%, respectively. Molecular gene analysis (rt-PCR) indicated that UVA-1 phototherapy activated specific antifibrotic pathways and reduced profibrotic pathways, notably through the overexpression of IL-1ß. This therapy also contributed to the stabilization of collagen synthesis. In a 2020 cross-sectional study, Chia et al. [17] investigated UV-A1 phototherapy in 17 patients with SSc. Positive treatment responses were documented in 11.8% and 10% of patients after 10 and 20 sessions, respectively, with response rates increasing to 40% after 30 sessions. The findings suggest that UV-A1 phototherapy is associated with partial clinical improvements and may necessitate prolonged treatment durations. Pruritus and erythema were the most frequently reported side effects.

A 2020 cohort study by Zbiciak-Nylec et al. [14] compared the effects of UV-A1 phototherapy (as photochemotherapy) and penicillin in 41 patients with morphea. The group receiving photochemotherapy showed a greater increase in measured particle levels (mean: 106.25ng/mL) than those given penicillin (mean: 81.50ng/mL). Furthermore, significant reductions in sTNFαR1 concentrations were documented in patients treated with PUVA, alongside notable improvements in clinical status following therapy. In a 2017 cross-sectional study by Attili et al. [19] investigating the efficacy of UV-A1 phototherapy QZ in 37 patients with morphea, phototherapy demonstrated positive therapeutic effects in 19 patients (51%). The study suggests that UV-A1 phototherapy is a viable treatment option for selecting dermatoses, with the treatment being well tolerated and no patients discontinuing due to adverse events. However, the risk of long-term malignancy remains uncertain.

In a 2014 cohort study by Vasquez et al. [20] involving 37 morphea patients treated with UV-A1 phototherapy, 46% experienced recurrence of active morphea lesions after successful UVA1 treatment. The recurrence rates at two- and three-year post-treatment were 44.5% and 48.4%, respectively. A significant association was found between recurrence and the duration of morphea before UVA1 therapy (P = 0.02), indicating that longer disease duration before treatment increases relapse risk.

The retrospective study by Malewska-Woźniak et al. compared the effectiveness of PUVA (psoralen + ultraviolet A) and UVA1 phototherapy in treating morphea. The results showed that both treatments led to significant clinical improvement, with a reduction in the clinical score for all patients. However, no significant differences in treatment response rates were observed between the two therapies. The study concluded that both PUVA and UVA1 are effective treatments for morphea with disseminated lesions, with UVA1 offering the added benefit of being free from the side effects commonly associated with oral psoralens, such as nausea and vomiting [22].

The study by Su et al. evaluated the therapeutic effectiveness of medium-dose (30 J/cm²) UVA1 phototherapy in 35 patients with morphea. The results showed marked clinical improvement in 82.85% of patients, along with a significant reduction in skin thickness, as measured by ultrasound. No side effects were reported during or after treatment. The authors concluded that medium-dose UVA1 is a safe and highly effective treatment for morphea, including all subtypes of the disease [23].

The study by Andres et al. assessed the efficacy of UVA1 phototherapy in 30 patients with morphea, including both a retrospective cohort (n = 17) and a prospective cohort (n = 13). In the retrospective study, medium-dose UVA1 was administered 6 months to 3 years prior, with 82% of patients reporting symptom improvement. The prospective study showed a 77% increase in skin elasticity and a 13% reduction in skin thickness after treatment. The study also observed significant changes in collagen metabolism, including elevated levels of collagen I and III metabolites. The authors concluded that UVA1 phototherapy provides both short- and long-term benefits, reducing sclerotic plaques, improving skin elasticity, and safely modulating collagen metabolism in morphea patients [24].

Systemic sclerosis

The retrospective study by Connolly et al. evaluated the use of UVA1 phototherapy in 83 patients with various sclerosing skin disorders, including systemic sclerosis (SS), graft-versus-host disease (GVHD), and nephrogenic systemic fibrosis (NSF). The study found that high-dose UVA1 phototherapy was most effective in improving clinical outcomes, particularly for GVHD and NSF, with improvements observed in 92.9% and 85.7% of patients, respectively. For systemic sclerosis, medium- and high-dose regimens showed significantly higher response rates compared to low-dose UVA1. The study concluded that UVA1 phototherapy is a safe and effective treatment modality, with a dose-response relationship observed in the management of these sclerosing conditions. High-dose UVA1 was particularly beneficial for GVHD and NSF, while medium and high doses were recommended for systemic sclerosis [25].

Treatment with fibroblast activation protein targeted photodynamic therapy

Systemic sclerosis

In a 2021 clinical trial, Dorst et al. [16] investigated the efficacy of Fibroblast Activation Protein-Targeted Photodynamic Therapy (FAP-tPDT) in 25 patients with SSc. The study showed that FAP-tPDT induced antibody-dependent, dose-related cytotoxicity in primary skin fibroblasts when exposed to light. In contrast, fibroblasts not exposed to light or treated with an unrelated photosensitizer antibody construct showed no response. Significantly, this therapy completely prevented the contraction of collagen grafts implanted with primary fibroblasts. Even at very low concentrations (0.4 nM), the antibody inhibited cell contraction derived from 2 out of 3 donors. This study was the first to show the potential of FAP-tPDT in controlling skin symptoms of systemic sclerosis by selectively depleting activated fibroblasts that drive fibrosis.

Treatment with a custom-made device containing infrared (850 nm), red (660 nm), and violet (405 nm) LEDs.

Systemic sclerosis

In a 2019 clinical trial, Hughes et al. [18] evaluated the efficacy of a custom-made device containing infrared (850 nm), red (660 nm), and violet (405 nm) LEDs in 8 patients with SSc. The study revealed substantial reductions in patient-reported pain, as assessed by the Visual Analog Scale (VAS), with mean changes of −7.1 and − 5.2, respectively, both reaching statistical significance (P < 0.001). Additionally, wound perfusion significantly increased following irradiation. The results indicate that this LED-based radiation therapy for digital ulcers is safe, feasible, and well tolerated.

Treatment with Water-Filtered infrared a plus visible light

Systemic sclerosis

In a 2011 case series study by Felbert et al. [21], the effectiveness of water-filtered infrared A plus visible light (wIRA + VIS) therapy was assessed in 10 patients with SSc who had not responded to conventional treatments. The therapy resulted in significant and lasting improvement in 7 patients. Among the remaining, one patient experienced a reduction in sclerosis and disease activity during treatment, but worsened after stopping the therapy. In two patients, for whom prior UVA1 treatment had failed, wIRA + VIS produced only a slight reduction in sclerosis without notable effects on disease activity. Overall, wIRA + VIS appeared effective in reducing skin sclerosis and controlling disease progression in CS, with treatment being well tolerated and no adverse events reported.

Treatment with ablative fractional laser

Morphea

The study by El-Shahawy et al. compared the effects of fractional CO2 laser and microneedling on 30 patients with morphea. The results showed significant improvements in both treatment groups, with reductions in clinical scores (LoSCAT) and histopathological improvements observed. The fractional CO2 laser group demonstrated slightly better results in terms of collagen remodeling, while both treatments resulted in high patient satisfaction. No major side effects were reported in either group, and both treatments were considered safe and effective for managing morphea [26].

This study by Guo Q et al. evaluated the efficacy and safety of ablative fractional laser (AFL) combined with methotrexate (MTX) delivery in 22 adults with morphea. The results demonstrated that both treatments were effective, with the AFL + MTX group showing significantly better outcomes in clinical appearance and dermal thickness compared to the AFL-only group. The clinical response, as measured by improved skin texture and reduced lesion size, was statistically significant (p = 0.042 for clinical appearance, p = 0.016 for dermal thickness). The combination therapy also proved to be safe, with no serious adverse effects reported during the study period [27].

The randomized controlled trial by Shalaby et al. involved 17 patients with morphea who received either fractional CO2 laser or low-dose UVA-1 therapy for their lesions. The results showed that fractional CO2 laser was significantly more effective than low-dose UVA-1 in improving clinical scores, collagen homogeneity, and patient satisfaction. Specifically, the CO2 laser group demonstrated a significant reduction in clinical scores (p = 0.001) and better improvement in collagen remodeling (p = 0.012). Patient satisfaction was also significantly higher in the CO2 laser group (p = 0.001), making it a superior treatment option for morphea compared to UVA-1 [28].

3.2. Intralesional injections

A review evaluating the effectiveness and safety of intralesional injections for treating morphea and systemic sclerosis (SSc) included 13 studies. The most frequently used intralesional treatments were stromal vascular fraction (SVF) gel (2 studies, 15.4%), fat micrografts combined with fat-derived SVF (1 study, 7.7%), Botulinum toxin (BTX) (4 studies, 30.8%), ozone/oxygen injections (1 study, 7.7%), hyaluronic acid fillers (2 studies, 15.4%), PRP combined with autologous SVF (1 study, 7.7%), Hydrodissection with an 80 mg injection of triamcinolone acetonide (1 study, 7.7%), and autologous fat grafting (1 study, 7.7%).

SVF (stromal vascular fraction) injection

Morphea

In a 2024 clinical trial by Liu et al., [29] the efficacy of injecting stromal vascular fraction (SVF) gel at 1 and 2 months following sequential fat grafting evaluated in 44 patients with morphea. At 12 months, the mean (SD) modified Localized Scleroderma Skin Severity Index (mLoSSI) score decreased by 1.6 (1.50), while the mean (SD) Localized Scleroderma Skin Damage Index (LoSDI) score decreased by 4.3 (1.34). These results indicate significant improvement in skin lesions, although disease activity did not substantially decrease. Histological examination verified increased skin regeneration alongside a reduction in skin sclerosis. The study demonstrated that sequential grafting of frozen fat combined with SVF gel is safe, with histological and transcriptomic findings supporting its therapeutic efficacy. The trial did not document any serious adverse events throughout its duration.

Systemic sclerosis

In a clinical trial by Iglesias et al. [30], which aimed to assess the efficacy of treating patients with systemic sclerosis using injections of fat micrografts plus fat-derived stromal vascular fraction (SVF) into the hands, 20 patients were studied. Study’s conclusion, significant reductions in pain levels were documented with statistical significance. The procedure proved to be reproducible and safe, providing an effective adjunct to conventional medical treatments for managing pain and finger ulcers in systemic sclerosis patients. No side effects were reported. Similarly, a 2017 clinical trial by Virzi et al. [35] assessed the effectiveness of platelet-rich plasma (PRP) injections combined with autologous SVF in 6 patients with systemic sclerosis. The treatment improved buccal contour, increased skin elasticity, and enhanced vascularization in all participants. This novel regenerative strategy demonstrates potential as a therapeutic option for chronic connective tissue disorders, including systemic sclerosis.

In a 2014 clinical trial by Granel et al. [38], the effectiveness of autologous SVF injections was investigated in 12 patients diagnosed with systemic sclerosis. The treatment significantly improved hand disability, pain, Raynaud’s phenomenon, finger edema, and overall quality of life. The study demonstrated that autologous SVF injections in the hands of systemic sclerosis patients are safe. Initial six-month assessments indicate promising efficacy, but these findings require confirmation through larger, randomized, placebo-controlled trials. No serious adverse events occurred during the procedure or follow-up period; four minor adverse events were reported, and all resolved spontaneously.

Botulinum toxin A injection

Systemic sclerosis

In a 2022 clinical trial by Shenavandeh et al. [31] involving 26 patients with systemic sclerosis divided into two groups, the efficiency of botulinum toxin A (BTX-A) injections was compared to prostaglandin analog infusions (iloprost or alprostadil). The first group received 20 units of BTX-A injected at the base of each affected finger, while the second group received 20 micrograms of iloprost or 60 micrograms of alprostadil daily. Wounds healed in 95.5% of fingers treated with BTX-A, and 90.5% in the prostaglandin group. Both groups experienced significant reductions in pain, and capillaroscopy showed notable decreases in microhemorrhages. The BTX-A group exhibited markedly decreased treatment costs and time savings as an outpatient procedure. One patient (4.5% of fingers) in the BTX-A group developed a localized finger infection, which resolved with oral and topical antibiotics. The prostaglandin group did not report any significant complications.

In a 2020 clinical trial, Lautenbach et al. [33] assessed the efficacy of botulinum toxin A (BTX-A) injections in 7 patients with systemic sclerosis, who received a mean dose of 90 units per hand. Among the 31 wounds treated across all patients, 77% (n = 24) healed, with a median time to wound closure of 8 weeks. The median duration of wound-free intervals was 8 months. Improvement in blood flow and pain reported in 60% of cases. The study concluded that BTX-A injections may benefit selected systemic sclerosis patients with chronic and refractory wounds; however, a larger, prospective study with adequate power is needed to provide definitive evidence.

In a 2017 clinical trial by Motegi et al. [36], the efficacy of botulinum toxin B (BTX-B) injections was evaluated in 45 patients with systemic sclerosis, allocated into four groups, comprising a no-treatment control group alongside treatment cohorts administered 250, 1,000, or 2,000 international units (U) of BTX-B injected into the hand. The study concluded that BTX-A injections may benefit selected systemic sclerosis patients with chronic and refractory wounds. However, larger prospective studies with adequate power are necessary to provide definitive evidence. These improvements lasted up to 16 weeks following a single injection. Additionally, the number of digital ulcers significantly reduced in the 1,000 and 2,000 U groups. Skin temperature recovery notably improved in 4 weeks in the 2,000 U group. The only reported adverse event was a transient muscle weakness in one patient in the 2,000 U group, lasting from 5 days to 3 weeks. No serious systemic or local adverse effects—such as anaphylaxis, dysphagia, dry mouth, or abnormal liver function—were documented. Although injection pain was common, it resolved within hours.

Systemic sclerosis, and morphea

In a 2017 randomized, double-blind, placebo-controlled clinical trial, Bello et al. [37] investigated the efficacy of botulinum toxin A (BTX-A) injections in 40 patients with scleroderma-associated Raynaud’s phenomenon, including 25 with Morphea and 15 with SSc. Each patient received 50 units of BTX-A diluted in 2.5 ml sterile saline injected into one hand, with the opposite receiving placebo saline injections. At the 1-month follow-up, the BTX-A–treated hands showed a markedly greater decrease in mean blood flow compared to placebo-treated hands, a difference mainly driven by patients with SSc and longstanding Raynaud’s phenomenon. However, by 4 months, alterations in blood flow did not differ significantly among the groups. Secondary clinical outcomes, including pain and functional scores, showed slight but questionable improvements. Two participants (5%) developed weakness in the intrinsic hand muscles following BTX-A injections; no muscle weakness was reported in placebo-treated hands.

Treatment with ozone/oxygen injection

Systemic sclerosis

In a 2020 clinical trial, Elawamy et al. [32] evaluated the effectiveness of ozone and methylprednisolone injections in 50 patients with systemic sclerosis. The researchers separated participants into two groups: Group O received injections of ozone/oxygen (25 µg/ml in 20 ml), and Group M received injections of methylprednisolone acetate (40 mg) combined with lidocaine (40 mg in 20 ml), both administered into the carpal tunnel. Pain levels measured by the Visual Analog Scale (VAS) were significantly lower in Group M after 1 week, while Group O showed substantially lower VAS scores in 3 and 6 months. Furthermore, both groups showed a significant reduction in VAS compared to baseline throughout the study period. The ozone group demonstrated appreciably decreased Carpal Tunnel Hand Function Scale (CHFS) scores at 6 months. Additionally, the ozone group experienced substantial reductions in distal motor latency at 3 and 6 months.

Treatment with hyaluronic acid filler injection

Morphea

The study by Owczarczyk-Saczonek et al. investigated the use of hyaluronic acid (HA) fillers in correcting facial morphea lesions. Three female patients, aged 16, 17, and 70, received HA injections (Juvéderm Voluma or Volux) to address facial lesions caused by morphea. The procedure involved injecting 0.5 ml of HA per side using a 25G cannula and 27G needle. Following the treatment, significant improvements were observed, with the Localized Scleroderma Damage Index (LoSDI) score reducing from an initial average of 7 to 3, reflecting a 57% reduction in skin damage. Over a follow-up period of 6 months to 3 years, no progression of the disease was observed, and the patients reported high satisfaction with the cosmetic outcomes. In one case, a combination of HA injections and fractional ablative CO2 laser (FAL) therapy was used, which further enhanced the aesthetic results by improving skin texture and reducing fibrosis. The study confirmed that HA injections, either alone or in combination with FAL, are safe and effective for improving the appearance of morphea lesions, with minimal adverse effects and sustained positive results over time [40].

Treatment with hyaluronic acid filler and platelet-rich plasma injections

Systemic sclerosis

In a 2019 clinical trial, Pirrello et al. [34], evaluated the effectiveness of three injections of hyaluronic acid filler combined with platelet-rich plasma (PRP), given at 15- to 20-day intervals, in 10 patients with systemic sclerosis. Patients showed notable improvement after the first injection, with benefits maintained for up to two years. Specifically, eight patients (80%) experienced increased mouth opening and upper lip thickness at the 1-month follow-up, and these improvements persisted through the 2-year mark. All patients exhibited increases in the distance between the upper and lower incisors, inter-commissural distance, and lower lip thickness at 1 month, with these enhancements maintained through 24 months. An increase in skin elasticity was also observed one month after completing treatment. The study suggests that hyaluronic acid filler combined with PRP injections is an effective treatment alternative for patients with SSc, significantly enhancing their quality of life.

Treatment with triamcinolone injection

Systemic sclerosis

In a 2011 clinical trial, DeLea et al. [39]., evaluated 12 patients with systemic sclerosis to assess the efficacy of hydrodissection combined with an 80 mg injection of triamcinolone acetonide. This treatment led to a substantial 67% decrease in pain scores among patients with SSc. Additionally, it alleviated pain and vasomotor symptoms affecting the hands. The therapeutic effect likely results from a combination of mechanical release of arteries, nerves, and tendons through hydrodissection, along with the reduction of inflammatory vasospasm induced by corticosteroids. The study reported no complications.

Treatment with autologous fat grafting

Morphea

The study conducted by Baserga et al. was a nonrandomized controlled trial involving 18 patients diagnosed with head-variant linear morphea. The mean age of the participants was 33 years, with an age range from 14 to 75 years. Patients underwent autologous fat grafting (lipofilling), with either one or two surgical treatments depending on their condition. The results showed significant improvements in facial symmetry as measured by stereophotogrammetry. At T1, the middle facial third exhibited a significant reduction in asymmetry, with RMS values decreasing from > 1.00 mm to < 0.80 mm. At T2, both the upper and lower facial thirds showed similar improvements, with RMS values aligning with those of healthy controls. The z-scores for all facial thirds significantly improved, indicating a marked reduction in facial asymmetry. Safety was also assessed, with no serious adverse events (AEs) such as infection or necrosis reported. Minor adverse events, including pain, skin irregularities, and paresthesia, were observed but resolved within the follow-up period [41].

Discussion

The management of morphea and systemic sclerosis (SSc) remains challenging because of concerns about disease reactivation after procedures and the scarcity of robust data on newer interventions such as energy-based devices and intralesional injections [42–44]. In this context, our systematic review synthesized the available evidence from 28 studies, including 15 evaluating energy-based modalities and 13 investigating intralesional therapies, to clarify their potential role and limitations in clinical practice.

Overall, the evidence for energy-based devices, particularly phototherapy with UVA-1, was limited and inconsistent. UVA-1 was the most frequently studied modality, yet the reported outcomes ranged from partial clinical improvement to high recurrence rates after treatment [14, 15, 20, 21]. For example, some observational studies suggested that prolonged courses of UVA-1 may lead to partial softening of lesions and improvement in skin texture, whereas others with longer follow-up periods reported substantial relapse after an initial response [14, 20, 21]. These discrepancies likely reflect differences in study design, disease stage and subtype, treatment regimens, and follow-up duration. Importantly, although no life-threatening adverse events were reported in the available studies, sample sizes were small and safety outcomes were not uniformly or systematically captured, so rare but serious complications or delayed disease reactivation cannot be excluded.

The biological plausibility of phototherapy in SSc and morphea is supported by its capacity to modulate fibroblast activity and cutaneous immune responses. UVA-1 has been shown to increase the expression of collagenase genes and their corresponding mRNA and protein levels in fibroblasts, and to exert immunomodulatory effects through the generation of reactive oxygen species and subsequent changes in cytokine profiles [14, 15]. These mechanisms may partly explain the clinical softening of sclerotic plaques reported in some studies [20, 21]. Nevertheless, based on the limited available data, current UVA-1 protocols (typically 20–50 J/cm² administered several times per week for around 30 sessions) should still be regarded as empiric, and the optimal dose, duration, and treatment window in the disease course remain uncertain [14, 20].

The results demonstrate the significant effectiveness of ablative fractional laser treatments in managing morphea. The fractional CO2 laser has shown notable improvements in clinical scores (LoSCAT) and histopathological outcomes, with better results in collagen remodeling compared to other treatments [26, 28]. Ablative fractional laser combined with methotrexate (MTX) has also proven to be more effective, with significant reductions in skin lesions and improvements in dermal thickness [27]. Furthermore, fractional CO2 laser outperforms low-dose UVA-1 in improving clinical scores, collagen homogeneity, and patient satisfaction [28]. Across all studies, these treatments have maintained a consistent safety profile, with no serious adverse effects reported. Overall, ablative fractional lasers, especially when combined with therapies like MTX, emerge as a superior, safe, and effective treatment option for morphea [26–28].

In contrast to energy-based devices, intralesional injections showed a more consistently positive signal across the included studies, although the overall certainty of evidence remains low [30, 32, 39]. With the exception of one trial, most reports of intralesional stromal vascular fraction (SVF) or botulinum toxin type A (BTX-A) described clinical improvement in skin induration, flexibility, pain, or functional impairment [30, 31, 35]. In particular, BTX-A injections in systemic sclerosis were associated with greater improvement in some functional outcomes compared with local control injections [31]. Similarly, SVF-based approaches appeared to be beneficial in localized sclerotic lesions, possibly by combining adipose-derived regenerative effects with local immunomodulation [30, 35]. However, these studies were generally small, often uncontrolled, and heterogeneous in terms of injection protocol, outcome measures, and follow-up duration. As a result, while intralesional therapies can be considered promising, they should still be classified as experimental rather than established standard treatments.

From a safety perspective, none of the studies on either energy-based devices or intralesional injections reported life-threatening adverse events. This is reassuring, particularly in a disease context where clinicians are understandably cautious about any intervention that might exacerbate inflammation or trigger disease reactivation. Nonetheless, the lack of standardized safety reporting, the relatively short follow-up in many studies, and the small sample sizes mean that the true risk profile is not fully defined. Clinicians should therefore continue to apply these modalities in carefully selected patients, ideally within specialized centers and, when possible, in the framework of clinical studies or registries.

The apparent discrepancy between mixed results for energy-based modalities and the more favorable outcomes reported with intralesional injections underscores the need for cautious interpretation. Our findings suggest that intralesional therapies may offer a more consistent short-term clinical benefit than energy-based devices, but the evidence is still insufficient to support strong, definitive recommendations. Any conclusion regarding “favorable” outcomes should explicitly acknowledge that the current data are preliminary, derived from small and methodologically heterogeneous studies, and that longer-term efficacy and safety remain to be established.

This review also highlights several important gaps in the literature. First, there is a need for well-designed, adequately powered randomized controlled trials comparing energy-based devices and intralesional injections with standard-of-care systemic or topical therapies, as well as with each other. Second, future studies should employ standardized and validated outcome measures, including clinical scores of skin induration and lesion activity, imaging-based assessments (such as ultrasound), and patient-reported outcomes related to function and quality of life. Third, longer follow-up periods are essential to determine the durability of treatment responses and to capture late relapses or delayed adverse events. Finally, mechanistic studies integrating histologic, molecular, and transcriptomic analyses would help clarify how these modalities influence the underlying pathophysiology of morphea and SSc and could guide the development of more targeted protocols.

Limitations

A key limitation of this study is the relatively small number of included studies [28], which may limit the broader applicability of the findings, especially for less common types of morphea and systemic sclerosis. Additionally, the studies included in this review varied in design, with a combination of clinical trials, cohort studies, and cross-sectional studies, making direct comparisons between interventions challenging. The follow-up durations in the studies were also inconsistent, ranging from as short as 5 days to as long as 37 months, which may affect the assessment of long-term treatment effects. Moreover, many of the studies were observational or non-randomized, which could introduce potential biases in how participants were selected or treatments were allocated. While most studies reported favorable treatment outcomes, there was insufficient and inconsistent reporting on adverse effects, limiting the ability to fully evaluate the safety of the treatments. The exclusion of non-English language studies could have introduced language bias, and the focus of the included studies was primarily on short-term outcomes, leaving gaps in understanding the durability of the results. Lastly, the variation in outcome measures used across studies made it difficult to make direct comparisons of the effectiveness and safety of the interventions.

Conclusion

In this systematic review, we examined the effectiveness and safety of various therapeutic interventions for the treatment of morphea and systemic sclerosis, including energy-based devices and intralesional injections. While the results suggest promising improvements in clinical outcomes, such as skin thickness reduction and enhanced quality of life, the evidence remains limited by the small number of included studies and variability in study designs. The findings highlight the potential of these therapies but should be interpreted with caution, particularly considering the short-term follow-up and the inconsistent reporting of adverse effects. Further well-designed, long-term randomized controlled trials are needed to confirm the efficacy and safety of these interventions and provide more robust evidence for clinical practice.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Contributions to the current study includes A.J. and A.L. and A.G. in study idea and design and in the literature review, and drafting and revising the manuscript critically for importance intellectual content. A.J. and A.L. in drafting the revised manuscript and literature review, and analysis and interpretation of revised version and drafting the manuscript. A.G. in the proposal preparation and statistics and analysis and drafting the revised manuscript. A.G. and A.J. in the study supervision, data gathering and literature review. All authors have read and approved the final version to be published and agreed to be accountable for all aspects of the work. All authors agreed on the order in which their names are listed in the revised manuscript.

Funding

No funding was received for writing this manuscript.

Data availability

All data generated or analysed during this study are included in this published article or as supplementary information files.

Declarations

Ethical approval

The Ethics Committee has waived the requirement for ethical approval, as this article is based on previously conducted studies and does not contain any new studies involving human participants or animals conducted by any of the authors.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Clinical trial number

Not applicable.