The efficacy and safety of tocilizumab in juvenile localised scleroderma patients: a retrospective cohort study in Eastern China

Abstract

Background

Localised scleroderma is a rare autoimmune connective tissue disorder characterized by excessive collagen deposition leading to skin fibrosis. While methotrexate and glucocorticosteroid remain the first-line treatments, their limitations underscore the need to explore targeted biologic therapies. Tocilizumab, an IL-6 receptor antagonist, has shown promise in some systemic autoimmune diseases, but its role in juvenile localised scleroderma remains unclear. This study retrospectively evaluates the efficacy and safety of tocilizumab in juvenile localised scleroderma patients.

Methods

This retrospective study analysed 12 juvenile localised scleroderma patients treated at Anhui Province Children’s Hospital between January 2021 and December 2024. Patients were grouped based on early versus delayed initiation of tocilizumab. Clinical response was measured using mLoSSI and LoSDI scores. Laboratory markers (ALT, AST, cholesterol, triglycerides, CRP) and immune indicators (CD4, CD19, IgG) were assessed alongside treatment duration. Safety and glucocorticosteroid usage were also evaluated.

Results

Five patients received tocilizumab from treatment onset, while seven were treated later. The tocilizumab initial use group had a significant lower relapse rate, compared to the delayed group. Longer treatment with tocilizumab had a protective effect on liver function and lipid metabolism, due to less abnormal ALT and triglyceride. No statistically significant relationship was observed between IgG deficiency and the duration of tocilizumab therapy; only one patient developed IgG deficiency, which resolved after a three-week interruption of treatment. Tocilizumab also reduced glucocorticosteroid reuse and duration of usage.

Conclusion

Tocilizumab appears to be a safe and effective adjunctive therapy for juvenile localised scleroderma, particularly when initiated early, as it reduces relapse risk and the need for prolonged glucocorticosteroid use. It remains a promising adjunct in refractory or severe cases requiring long-term management.

Supplementary Information

The online version contains supplementary material available at 10.1186/s42358-025-00511-1.

Introduction

Localised scleroderma, also known as Morphea, is a rare chronic autoimmune connective tissue disease characterized by excessive collagen deposition in the dermis and subcutaneous tissues [1]. Unlike systemic sclerosis, Localised scleroderma primarily affects the skin and underlying structures without systemic involvement. The disease progresses through distinct stages, beginning with an inflammatory phase marked by erythematous and violaceous lesions, which later evolve into sclerotic plaques and skin atrophy [2]. Depending on the severity and depth of involvement, localised scleroderma can cause significant cosmetic disfigurement, functional impairment, and, in some cases, damage to underlying muscles and bones. The clinical presentation includes several subtypes such as circumscribed, linear, generalized, pan sclerotic, and mixed forms [3].

Juvenile localised scleroderma is a rare disease, with an estimated annual incidence of one to three cases per 100,000 [4, 5]. Juvenile localised scleroderma accounts for approximately 25% of all localised scleroderma cases and primarily affects children between the ages of two and fourteen years [6]. The mean age of onset is six to nine years, with a strong female predominance (female-to-male ratio of 2.4:1 to 6:1) [7, 8]. While the disease affects all ethnicities, it appears more common in Caucasians [9, 10]. Up to 20% of paediatric patients experience extracutaneous manifestations, including arthritis, uveitis, seizures, and neurological complications. Juvenile localised scleroderma tends to follow a chronic relapsing-remitting course, with recurrence rates as high as 45%. Without early and aggressive treatment, it can lead to permanent deformities and long-term disability [11].

The pathogenesis of localised scleroderma is multifactorial, involving genetic predisposition, autoimmune dysregulation, and environmental triggers such as infections and trauma [12]. The disease process begins with endothelial cell damage, which releases the cytokine like IL-6. This inflammatory signal promotes fibroblast activation, resulting in excessive collagen production and tissue fibrosis. The fibrotic process causes dermal sclerosis, vascular compromise, and skin appendage atrophy, leading to irreversible damage if left untreated [13, 14].

Traditional treatment focuses on controlling inflammation and preventing fibrosis progression. Methotrexate, in combination with glucocorticosteroid, is considered the first-line systemic therapy for juvenile localised scleroderma due to its efficacy in reducing disease activity and preventing relapses However, methotrexate and glucocrticosteroids are associated with numerous side effects, including hepatotoxicity, immunosuppression, and growth retardation in children [15]. The long-term efficacy of these treatments is inconsistent, with many patients experiencing relapses once therapy is tapered or discontinued. Furthermore, these therapies primarily target inflammation but fail to address the underlying fibrotic processes. This can lead to permanent tissue damage despite adequate control of inflammation [8]. Tocilizumab, an IL-6 receptor antibody, has shown promise in treating refractory Localised scleroderma. This advanced therapy aims to modulate specific immune pathways more effectively than traditional immunosuppressants [16]. It is considered a potential treatment option for localized scleroderma with predominant extracutaneous involvement, particularly when standard therapies like methotrexate and glucocorticosteroid have failed or are contraindicated [17]. However, this is recommended based on expert opinion without a formal strength of recommendation. The long-term safety and efficacy data in juvenile localised scleroderma treatment are lacking. Therefore, this retrospective study is to evaluate the efficacy and safety of tocilizumab in juvenile localised scleroderma patients who received this antibody-based treatment for at least six months.

Methods

Subjects

The medical record of patients, diagnosed as Juvenile localised scleroderma in Anhui Province Children’s Hospital from January 2021 to December 2024, were reviewed [13, 18]. The inclusion criterion were: patients receiving the tocilizumab therapy, patients with the Localised Scleroderma Skin Damage (LoSDI) and the modified Localised Scleroderma Skin Severity Index (mLoSSI) assessments at each out-clinic visit, and their follow up longer than three-month period [19, 20]. The exclusion criterion were: uncompleted records, patients with other diagnosis, patients with congenital disorders, patients with abnormal liver or renal function before therapy, and the patient or their guidance refusal.

Ethics approval

This retrospective study was approved by the Ethics Committee of Anhui Province Children’s Hospital (approval No. EYLL-2025-049). Because the cohort included minors, written informed consent was obtained from each participant’s parent(s) or legal guardian(s). In addition, age-appropriate assent was sought and obtained from child participants in accordance with local regulations and the institution’s policy; for any participant who had reached the age of majority at the time of consent, written informed consent was obtained directly from the participant. All procedures complied with the Declaration of Helsinki and relevant guidelines.

Screening and assessment

The enrolled patient records were scanned by two paediatric specialists (YS and JS), separately. Then, the related data and results were extracted. Complete response to treatment was defined as reaching an mLoSSI of 0 (inactive disease). Time Length of Complete Response (mLoSSI = 0), month was defined as the time interval (in months) from initiation treatment to the first visit at which the mLoSSI score reached 0. Relapse was defined as any increase above 0 on the mLoSSI. Persistent disease activity was defined as active disease at all study visits. Disease damage was assessed via LoSDI. The immune biomarker status was considered as normal or abnormal. The duration of Tocilizumab/corticosteroid use was measured as the continuous use from the begin to the end. Disease duration before tocilizumab was defined as the interval from first juvenile localised scleroderma symptom to first tocilizumab dose. Additionally, in this study, “tocilizumab initial use” was defined as initiating tocilizumab concurrently with the first systemic treatment for juvenile localised scleroderma. In contrast, “tocilizumab delayed use” referred to cases where tocilizumab was introduced only after multiple prior systemic treatments had been administered.

Statistical analysis

Means (SDs) and medians with interquartile ranges (IQRs) were calculated for continuous variables, while categorical variables were described using frequency counts and percentages. The primary outcome was the time to recurrence of juvenile localised scleroderma disease activity from the first visit with inactive disease. The time to recurrence was defined as the period between relevant follow-up visits. The status of each patient with active versus inactive disease were recorded and evaluated at each visit during follow-up. Disease damage progression over time was analysed using LoSDI, focusing on sclerosis, dermal atrophy, and subcutaneous atrophy. The relationship between tocilizumab treatment duration and biomarker status was assessed by categorizing tocilizumab treatment duration into high and low groups based on the median value. T-test, Fisher exact test, Mann-Whitney test, Chi-square test or Spearman’s rank correlation was used as appropriated, p value and odds ratio (OR) were measured. Statistical significance was set at p < 0.05, and all analyses were conducted using R software.

Results

The general information for the enrolled patients

Fourteen records were screened from January 2021 to December 2024, and 12 patients were enrolled, while two were excluded due to incomplete medical records. The enrolled patients were group into two as the one with tocilizumab initial use and the one with tocilizumab delay use. Tocilizumab was administered at 8 mg/kg every 4 weeks in 10/12 patients and 12 mg/kg every 4 weeks in 2/12 patients (both with mixed morphea), while the initial prednisone dose ranged 1–2/kg, then reduced based on the clinical improvement (median 0.4–0.8 mg/kg) (Supplementary matrerials).

The average age of the 12 patients at diagnoses was 6.92 years. There were six males and six females in this cohort. The average of baseline of height and weight were 135 cm and 38.14 kg, respectively. All of them were in normal growth. The medium duration of follow-up was 39.16 (3.23–131.5) months. The medium baseline of mLoSSI was nine (4–33); the medium of baseline of LoSDI was 11 (2–47). All patients had immunosuppressive agent treatment. Five had tocilizumab initial use. The delayed-use group (n = 7) had 3.2 months (IQR 1.5–5.4) before their tocilizumab use. All patients were with normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, triglycerides, and C-reactive protein (CRP).

The efficacy of tocilizumab

This study included 12 patients, where five patients received tocilizumab therapy initially, while seven patients were tocilizumab delay use (Table 1). One of the patients in the initial use group experienced treatment delay due to temporary IgG deficiency. The rest of the initial use group had no relapse case, whereas five out of seven patients (71.4%) in the delay group relapsed. Among the five patients who experienced relapse, four had not received tocilizumab prior to the relapse event. Moreover, no relapse case was observed after tocilizumab use. The results showed that the group of tocilizumab initial use had significant lower relapse rate than the delay one (P = 0.028). Patients in the delayed tocilizumab use group experienced a significantly longer median complete response (CR) duration (5.1 months, IQR: 3.1–8.6) compared to those who received tocilizumab from the start (1.8 months, IQR: 1.2–2.5), with the difference reaching statistical significance (p = 0.009).

Table 1.

Baseline information of the 12 patients

Group	Relapse	No Relapse		Corrected Odds Ration	Fisher’s Exact (two-tailed)	P-value
1	0	5
2	5	2
Statistical Results				0.2		0.028
Group	Median CR Duration (months)	IQR (Q1–Q3)		Sample Size	Mann-Whitney U Statistic	P-Value (Mann-Whitney)
1	1.8	1.2–2.5		5
2	5.1	3.1–15.3		7	1.0	0.009
Group	LoSDI decreased	LoSDI increased		LoSDI unchanged	Chi-square Statistic	P-Value
1	2	1		2
2	3	3		1
Statistical Results					1.23	0.53

1 = Tocilizumab in initial treatment

2 = No tocilizumab in initial treatment

CR, complete response

Chi-square test comparing the distribution of LoSDI change categories between groups; χ² (2) = 1.23, p = 0.53

Among patients who received tocilizumab initially, two had decreased LoSDI scores, two remained unchanged, and two had increased scores, whereas in the delay use group, three had decreased scores, one remained unchanged, and three had increased scores. The LoSDI changes were similar between the two groups, with no significant difference observed (p = 0.539).

The safety of tocilizumab

Across the 12 patients, longer tocilizumab duration was significantly associated with lower abnormal ALT (p = 0.009, OR = 0.19) and triglycerides (p = 0.009, OR = 0.37) levels (Table 2). No significant relationship was found for AST (p = 0.498, OR = 0.49) or cholesterol (p = 0.618, OR = 0.32). CRP analysis was statistically invalid due to a lack of abnormal cases, making it impossible to assess its relationship with antibody duration. Overall, ALT and triglycerides showed the most meaningful trends, while AST, cholesterol, and CRP exhibited no clear relationship with antibody duration. Moreover, one patient experienced an IgG deficiency, which was considered as tocilizumab-related. Following a withdrawal for three weeks, the patient fully recovered, and the treatment was subsequently resumed without further complications.

Table 2.

Liver function and CPR in the two groups

Biomarker	Odds Ratio	P-value	Confidence Interval (95%)
ALT	0.19	0.009	(0.05–0.68)
AST	0.49	0.498	(0.05–4.55)
Triglycerides	0.37	0.009	(0.18–0.78)
Cholesterol	0.32	0.618	(0.02–3.99)
CRP	N/A	1	(N/A)

ALT = alanine aminotransferase

AST = aspartate aminotransferase

CRP = C-reactive protein

The use of glucocorticosteroid

In this study, 12 patients were analysed, of whom 10 received glucocorticosteroid treatment. Among these 10, six patients (60%) experienced steroid reuse, and the remaining four successfully discontinued glucocorticosteroid (Table 3). Importantly, three of the four patients who successfully discontinued steroids were in the early tocilizumab treatment group, whereas all six patients who required steroid reuse had not received tocilizumab at disease onset. This showed a strong association between early tocilizumab intervention and reduced steroid reuse, a finding that reached statistical significance (p = 0.033). Regarding to the duration of steroid, the mean duration of steroid use in the tocilizumab initial use group was 4.27 ± 1 weeks, compared to 20.28 ± 8.5 weeks in the delay use group. A statistically significant difference was found in steroid use duration between the two groups (p = 0.002).

Table 3.

Glucocorticosteroid reuse in the two groups

Group	Reused Glucocorticosteroid	Non-Reuse Glucocorticosteroid	P Value
1	0	3
2	6	1	0.033

1 = Tocilizumab in initial treatment

2 = No tocilizumab in initial treatment

The association of antibody/glucocorticosteroid duration with cluster of differentiation 4 (CD4), cluster of differentiation 19 (CD19) and immunoglobulin G IgG abnormalities

Among the 12 patients, seven received immunosuppressive agent and tocilizumab during the monoclonal antibody therapy stage, while the remaining five were treated with a combination of immunosuppressive agent, tocilizumab and glucocorticosteroid (Table 4). No significant difference was found between tocilizumab duration and IgG normalization (p = 0.421). CD4 abnormality also had an inverse trend with tocilizumab duration (ρ = − 0.58, p = 0.063), suggesting a trend toward recovery of CD4 levels with longer treatment. No other significant correlations were observed between glucocortisteroid duration and any immune marker.

Table 4.

Tocilizumab and CD4, CD19, and IgG

Biomarker	Duration Type	Spearman ρ	P-value
CD4	Duration of tocilizumab use	-0.58	0.063
CD4	Duration of glucocorticosteroid use	0.18	0.589
CD19	Duration of tocilizumab use	-0.15	0.662
CD19	Duration of glucocorticosteroid use	0.14	0.677
IgG	Duration of tocilizumab use	0.25	0.421
IgG	Duration of glucocorticosteroid use	-0.18	0.589

Discussion

This study retrospectively evaluated the effectiveness and safety of tocilizumab in juvenile localised scleroderma, focusing on disease recurrence, biomarker alterations, and treatment-related adverse events. Our findings demonstrated that patients who received tocilizumab as an initial therapy had a lower relapse rate than those in the delay use group. Especially, of the five relapse cases, four occurred in patients who had not been treated with tocilizumab at the time of relapse. These findings align with the previous report that localised scleroderma follows a chronic, relapsing-remitting course, and tocilizumab administration can reduce relapse risk [21]. Immunosuppressive agent remains the first-line systemic therapy, often used in combination with glucocorticosteroid, given its proven efficacy in reducing disease activity and preventing relapses [15, 18]. The previous study showing that while IL-6 blockade plays a role in inflammatory control, it does not completely halt fibrotic progression in localised scleroderma, emphasizing that the treatment approach should address both inflammation and fibrosis simultaneously [22–25]. Given the heterogeneity of localised scleroderma subtypes and disease courses, these results highlight the importance of individualized therapeutic strategies, particularly in patients with rapidly progressive or refractory disease [24].

The evaluation of safety outcomes and biomarker changes revealed that longer tocilizumab use was significantly associated with lower abnormal ALT and triglycerides levels, suggesting a potential protective effect on liver function and lipid metabolism. These results align with previous research indicating that IL-6 inhibition can influence metabolic regulation, reducing systemic inflammation while modulating lipid and glucose homeostasis [26]. However, no significant associations were found for AST, cholesterol, or CRP, which suggests that tocilizumab’s metabolic impact may be selective, influencing some hepatic enzymes and lipid components but not others [27]. These findings are consistent with studies in rheumatoid arthritis, where IL-6 blockade has been linked to changes in lipid metabolism, with reports showing elevated LDL and total cholesterol levels in some patients receiving tocilizumab [28]. While IL-6 inhibitors may provide hepatoprotective benefits by reducing systemic inflammation, their effects on broader lipid and cardiovascular risk profiles remain uncertain [29]. Additionally, one patient in our study developed a pulmonary infection, which was considered tocilizumab-related. This supports previous findings that IL-6 inhibition increases susceptibility to infections due to its role in modulating immune responses [30]. Increased infection risks, particularly bacterial pneumonia and cellulitis, have been reported in long-term tocilizumab use, emphasizing the need for continuous infection monitoring [31]. These findings reinforce the necessity of careful patient selection and regular safety assessments in juvenile localised scleroderma patients undergoing tocilizumab therapy.

Glucocorticosteroid are one kind of key components in the therapeutic management of juvenile localised scleroderma, especially when systemic intervention is warranted. In clinical practice, they are frequently employed as initial bridging agents alongside systemic immunosuppressants such as methotrexate [17, 32]. Although specific data on glucocorticosteroid side effects in juvenile localised scleroderma is limited, studies in other paediatric conditions report significant risks such as obesity, pancreatic related issues, Cushing’s syndrome, and gastrointestinal issues [33–36]. Moreover, Long-term, high-dose glucocorticosteroid therapy during childhood and adolescence can impair growth and delay puberty by suppressing the hypothalamic–pituitary axis and reducing bone formation, particularly affecting spinal trabecular bone mineralization. These effects may lead to reduced adult height, delayed pubertal progression, and suboptimal peak bone mass despite intermittent recovery periods [37, 38]. Rare hypersensitivity reactions have also been documented, underscoring the need for careful monitoring and consideration of steroid alternative strategies in localised scleroderma management [39]. In this study, the early administration of tocilizumab group had significantly reduction in both the reuse and duration of glucocorticosteroid use, indicating a notable steroid-sparing effect. The prolonged glucocorticosteriod use is most likely related to the slower clinical improvement in the delay group. Due to the risks associated with long-term steroid use in paediatric patients, tocilizumab could be considered as an effective alternative to glucocorticosteroid in selected severe or refractory cases. Some previous case reports also suggested tocilizumab can effectively reduce disease activity in treatment-resistant localised scleroderma, including cases unresponsive to corticosteroids [21, 40, 41]. These findings support its role as a potential steroid-sparing alternative, minimizing the need for prolonged glucocorticosteroid use.

Tocilizumab has demonstrated promising safety and efficacy in treating refractory localised scleroderma across both adult and paediatric populations. In adults, a case series of three women with generalized or linear localised scleroderma showed complete or partial clinical response with improved erythema, softening of lesions, and functional outcomes, without significant adverse effects except mild hyperlipidaemia [41]. In paediatric, including a multicentre study of 11 children and two individual reports of pan sclerotic localised scleroderma, tocilizumab led to reduced disease activity and halted progression, even in patients unresponsive to methotrexate or mycophenolate [40, 42]. Treatment was well tolerated, with no serious complications reported. These findings support tocilizumab as a viable rescue therapy for severe or treatment-resistant localised scleroderma.

IL-6 plays a central role in the immunopathogenesis of localised scleroderma, influencing Th17 differentiation, fibroblast activation, and excessive collagen production [27]. Prior studies in rheumatoid arthritis and systemic sclerosis have demonstrated that IL-6 blockade can lead to increased regulatory T cells and decreased Th17 responses, potentially modifying disease progression [43]. However, in fibrosis-driven diseases like localised scleroderma, IL-6 inhibition alone may not be sufficient to reverse the relative symptoms, particularly in cases where fibrosis has already been established [44]. IL-6 blockade has been linked to modulating fibroblast activity and extracellular matrix remodelling, suggesting that tocilizumab may have beneficial effects beyond inflammation suppression. However, its role in reversing existing fibrotic damage remains unclear, as previous studies in systemic sclerosis have yielded mixed results regarding its effectiveness in reducing dermal sclerosis and improving skin elasticity. Findings from recent studies suggest that while IL-6 inhibition can reduce inflammatory markers and suppress collagen synthesis, it does not fully reverse established fibrotic lesions [25, 45, 46]. These observations suggest that tocilizumab may be more effective in preventing disease progression rather than reversing existing damage, and that combination therapies targeting both inflammation and fibrosis may be more effective in achieving long-term disease control.

Strength and limitation

This is a long-term retrospective clinical study on tocilizumab’s effects in juvenile localised scleroderma, suggesting potential benefits in metabolic regulation and disease management. The comparison between tocilizumab-treated and untreated patients highlights its possible role as an adjunct therapy, contributing to a better understanding of treatment response and disease progression. However, the small sample size, retrospective design, lack of fibrosis-specific assessments, and absence of disease/immunosuppressive agent subtype classification limit the generalisability of the findings and restrict the ability to fully evaluate treatment responses across different clinical variants. In future, a multi-centres prospective study should be considered with systematic recording across disease subtype to better understand treatment responses and prognosis.

Conclusion

Tocilizumab demonstrates potential as a steroid-sparing agent with favourable effects on liver function, lipid metabolism, and normalization of immunoglobulin levels in juvenile localised scleroderma. In this study, early initiation of tocilizumab was associated with a significantly lower relapse rate compared to late use, suggesting its potential benefit in maintaining disease remission. However, it did not significantly impact reverse established fibrosis. Its selective metabolic advantages and reduction in glucocorticosteroid exposure support its role as an adjunctive therapy, particularly in refractory or relapsing cases. Given its limitations in tissue remodelling, future research should investigate combination strategies targeting both inflammation and fibrosis. Larger prospective studies are needed to define its optimal use and long-term safety profile in juvenile localised scleroderma.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Denghuan, Chen, Yutong Gao, Shouwei, Hang, Xinrong Wang, Na Li, and Dingyun Chen contributed to data collection, analysis and interpretation; Jing Shan wrote the main manuscript; Yang Shen, Xiaoliang He and Daliang Xu reviewed, edited and approved the final manuscript.

Funding

Not applicable.

Data availability

No datasets were generated or analysed.

Declarations

Ethics approval and consent to participate

The study was approved by the Anhui Province Children’s Hospital review board (EYLL-2025-049), and written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.