[Academic Presentation] Recent Advances in the Study of Juvenile Systemic Sclerosis

Article reprinted from: Chinese Medical Abstracts – Dermatology, Issue 1, 2017.

Authors: Liu Ying, Chen Deyu, Xiong Xia

Juvenile systemic scleroderma, JSSc ) Also known as juvenile systemic sclerosis, it is a chronic connective tissue disease characterized by symmetrical skin thickening and hardening, along with fibrotic changes in multiple internal organs. It is clinically rare, and in its early stages often lacks typical clinical manifestations and specific diagnostic markers, making misdiagnosis common. Early diagnosis and effective treatment are crucial for improving the prognosis. This article discusses… JSSc diagnostic criteria, epidemiology, etiology and pathogenesis, clinical manifestations, and with Adult SSc A brief review of the differences, treatment, and prognosis is presented to enhance understanding of… JSSc Understanding, for clinical diagnosis and treatment JSSc Provide the basis.

1 Diagnostic Criteria

The new diagnostic criteria for juvenile systemic sclerosis (JSSc) were jointly developed in 2007 by the European Paediatric Rheumatology Society (PRES), the American College of Rheumatology (ACR), and the European League Against Rheumatism (EULAR). According to these criteria, patients under 16 years of age who meet one major criterion and at least two minor criteria are diagnosed with JSSc. The criteria encompass clinical manifestations involving skin and internal organ involvement, as well as relevant positive laboratory findings. Furthermore, they emphasize the importance of digital skin and distal interphalangeal joint involvement for diagnosis, whereas in adult systemic sclerosis (SSc), a diagnosis can be made even in the absence of skin involvement. With respect to sensitivity and specificity, these criteria have been validated in adult SSc patients; however, their applicability to JSSc still requires long-term clinical validation.

2 Epidemiology

Domestic and international literature indicate that among all patients with systemic sclerosis, those who develop the disease before age 16 account for less than 3%; juvenile systemic sclerosis (JSSc) is even rarer, with an incidence of approximately 0.5 per million. JSSc predominantly affects girls, with a male-to-female ratio of about 1:3.6; the mean age at onset is around 8 years, and the peak incidence occurs between 10 and 16 years. There is no clear racial predilection, though a familial clustering trend has been observed. JSSc often has an insidious onset, with atypical early symptoms that frequently lead to misdiagnosis; the time from symptom onset to definitive diagnosis varies, typically ranging from 1.9 to 2.8 years. Furthermore, systemic sclerosis diagnosed in childhood carries a higher risk of disability; in China, 80% of pediatric cases result in impaired physical function, significantly exceeding the 11%–44% reported in other countries. Scholars suggest that this discrepancy may be related to differences in the types of cases analyzed, the timing of initiation of standard treatment, and adherence to therapy.

3 Etiology and Pathogenesis

The etiology of JSSc remains unclear; its pathogenesis likely involves the combined contributions of multiple factors, with reported associations including autoimmunity, vascular injury, genetics, infection, trauma, inflammation, and abnormalities in collagen metabolism.

3.1 Autoimmunity

In patients with JSSc, a high positive rate of antinuclear antibodies (ANA) and the presence of various autoantibodies—such as anti‑centromere antibodies (ACA), anti‑SCL‑70 antibodies, anti‑PM‑Scl antibodies, and antibodies against soluble nuclear antigens (ENA)—have been observed in a subset of cases, suggesting that autoimmunity plays a significant role in its pathogenesis. Reiff et al. compared the numbers of T lymphocytes in peripheral blood between adult patients with systemic sclerosis and those with JSSc, finding that JSSc patients exhibit a reduced population of resting regulatory T lymphocytes and an increased expression of memory CD4 T lymphocytes. They hypothesize that the decline in resting regulatory T lymphocytes and the expansion of memory CD4 T lymphocytes may initiate the disease process in JSSc, implicating a potential role for cellular immunity in this condition.

3.2 Vascular Injury

Matucci‑Cerinic et al. reported that systemic sclerosis (SSc) is a primary vascular disease, in which patients often exhibit damage to small vessels in the extremities, manifesting as Raynaud’s phenomenon and abnormal findings on nailfold capillaroscopy. When larger vessels are involved, this may lead to severe skin ulcers, ischemic necrosis of the digits or limbs, and, concurrently, dysfunction of the heart, lungs, kidneys, and gastrointestinal tract. In most patients with juvenile systemic sclerosis (JSSc), Raynaud’s phenomenon likewise serves as the initial symptom, followed by peripheral microvascular dysfunction—such as digital swelling and abnormalities of the nailfold capillaries. Thus, vascular injury is also a key pathogenic factor in JSSc; potential mechanisms include: ① immune‑mediated cytotoxicity, anti‑endothelial antibodies, and ischemia–reperfusion injury leading to endothelial cell apoptosis; and ② an imbalance of vasoactive factors, characterized by increased production of vasoconstrictor endothelin and decreased production of vasodilators such as nitric oxide and prostacyclin. In JSSc patients, multiple pathogenic factors act upon the vasculature, inducing vascular damage, after which the vessels undergo fibrotic remodeling, resulting in tissue ischemia, fibrosis, and multiorgan dysfunction.

3. 3 Other

Histopathologically, JSSC is characterized by excessive deposition of uniform collagen fibers and infiltration of inflammatory cells, findings that resemble those observed in adult SSc patients, suggesting that inflammation and abnormal collagen metabolism also contribute to the pathogenesis of JSSc. A relatively high familial incidence may support a genetic component in disease onset, while the low concordance rate among monozygotic twins implies that genetic factors may play a minor role or involve complex polygenic mechanisms. Denton et al. have reported that infections and trauma are associated with the development of childhood scleroderma, potentially through immune activation and impaired scar healing. Furthermore, the higher prevalence in females suggests that estrogen‑mediated autoimmune predisposition and X‑chromosome inactivation mosaicism may represent additional pathogenic mechanisms. Nevertheless, the precise pathogenic mechanisms underlying JSSc remain to be elucidated through further research.

4 Clinical Manifestations

JSSc has two main subtypes: the diffuse type and the acral type. Patients with the diffuse form exhibit widespread skin involvement, characterized by progressive cutaneous thickening and early involvement of internal organs such as the lungs, heart, and kidneys. Clinical manifestations may include early swelling and pain in the hand and foot joints, followed by later-stage skin sclerosis, often accompanied by Raynaud’s phenomenon, joint pain and impaired mobility, tendinitis, myositis, and bone changes. In contrast, patients with the acral form present with localized, non‑progressive skin thickening and sclerosis, along with peripheral vascular involvement; they may develop pulmonary arterial hypertension or gastrointestinal malabsorption syndrome. The acral subtype is distinguished by prominent vascular involvement, primarily manifesting as Raynaud’s phenomenon, capillary abnormalities, digital pitting, volar digital atrophy, calcinosis, distal digital ischemic necrosis, and ulcers. Patients exhibiting features of CREST syndrome are also classified within this subtype. Additionally, approximately 27% of JSSc patients concurrently display features of other connective tissue diseases, such as dermatomyositis or systemic lupus erythematosus, a condition known as an overlap syndrome. According to the literature, 70% of JSSc patients present with Raynaud’s phenomenon as the initial symptom, with 10% developing distal digital ischemic necrosis. Skin changes at the fingertips, including edema and sclerosis, constitute the second most common manifestation, observed in 60% of cases. Throughout the disease course, Raynaud’s phenomenon and skin sclerosis remain the most frequent symptoms, affecting roughly 84% of patients, while respiratory symptoms occur in about 42%, gastrointestinal symptoms in approximately 30%, arthritis in around 27%, and cardiac involvement in roughly 15%. Renal crisis, renal failure, and central nervous system manifestations are exceedingly rare, accounting for approximately 3%, 5%, and 0.7%, respectively.

5. Differences from Adult SSc

The incidence of JSSc is approximately 3% to 10% of that in adults, with the diffuse form being more common, whereas in adult SSc, the limited form predominates. In JSSc, the prevalence of early arthritis and myositis, as well as the severity of Raynaud’s phenomenon, are higher than in adults; visceral involvement is markedly reduced, and by the later stages, these differences become less pronounced. Throughout the disease course, interstitial pneumonia, renal crisis, gastroesophageal motility disorders, arterial hypertension, and musculoskeletal symptoms are less frequent in JSSc patients compared with adults, while cardiac involvement is more common. Involvement of other internal organs is similar to that observed in adults. Furthermore, JSSc patients have a higher incidence of overlap syndromes but a lower rate of positive autoantibodies than adults. Overall mortality in JSSc is lower than in adults; cardiac involvement is the leading cause of death, manifesting as myocardial infarction, arrhythmias, congestive heart failure, and cardiomyopathy, whereas in adult SSc, pulmonary involvement—particularly interstitial lung disease and pulmonary arterial hypertension—is the primary cause of mortality.

6 Treatment

JSSc, owing to its unclear etiology, lacks a specific curative treatment; management is primarily symptomatic and supportive, focusing on anti-inflammatory therapy, improvement of circulation, immunosuppression, antifibrotic agents, and other measures to address associated symptoms.

6.1 Anti-inflammatory

Oral glucocorticoids can reduce inflammation and are used to treat active myositis, arthritis, and interstitial lung disease. The recommended dose is 0.3–0.5 mg/(kg·day) of prednisone. Because corticosteroid use may increase the risk of scleroderma renal crisis, blood pressure and renal function must be closely monitored.

6. 2 Improving Circulation

Calcium channel blockers (CCBs) can dilate blood vessels, relax vascular smooth muscle, reduce peripheral vascular resistance, and improve circulation. Nifedipine or nicardipine, typically administered orally, should be considered as first-line therapy for Raynaud’s phenomenon. Intravenous prostaglandins, such as iloprost—a prostacyclin analog—can dilate local vessels, suppress inflammation, and counteract vascular remodeling, making them useful for treating severe Raynaud’s phenomenon and digital ulcers. A recent study reported that intermittent intravenous iloprost infusion can safely and effectively manage patients with refractory Raynaud’s phenomenon and digital ulcers. Angiotensin-converting enzyme (ACE) inhibitors, including captopril and losartan, exert potent vasodilatory effects and are thought to provide long-term, effective blood pressure control while stabilizing renal function in patients with systemic sclerosis; however, their role in preventing scleroderma renal crisis remains unclear. In addition, targeted vascular agents—endothelin receptor antagonists (bosentan) and phosphodiesterase‑5 inhibitors (sildenafil)—are indicated for the treatment of pulmonary arterial hypertension; bosentan may also help prevent digital ulcers, though it does not mitigate pulmonary fibrosis.

6.3 Immune Suppression

Cyclophosphamide remains a subject of debate; despite its known toxicity and the lack of sustained long-term benefits, most experts still recommend its use in patients with JSSc who also have interstitial lung disease. For intravenous pulse therapy, the dose is 0.5–1 g/m² monthly, with a treatment course of at least six months. To prevent cystitis, adequate hydration and frequent urination are essential; prophylactic administration of mesna (sodium mercaptoethanesulfonate) can reduce bladder mucosal damage. Methotrexate is widely used in the management of numerous connective tissue diseases and can improve cutaneous manifestations in early‑stage diffuse systemic sclerosis in adults. It is now considered an option for treating JSSc, particularly in the early stages of the diffuse subtype. Subcutaneous methotrexate at 15 mg/m² daily represents a first‑line regimen for pediatric patients, with mycophenolate mofetil at 1,500 mg/(m²·day) added as needed to enhance efficacy, depending on disease progression.

6.4 Anti-fibrotic

Penicillamine inhibits collagen cross-linking and suppresses the synthesis of new collagen, thereby alleviating skin fibrosis. In children, the initial dose is 3 mg/(kg·day) for the first 2 months, followed by an incremental increase of 2 mg/(kg·day) per month, up to a maximum dose of 15 mg/(kg·day).

6. 5 Other

① Physical therapies such as massage and thermotherapy can promote microcirculation and improve skin symptoms.

② Proton pump inhibitors (PPIs), such as omeprazole and lansoprazole, can prevent gastroesophageal reflux disease and esophageal ulcers.

③ Prokinetic agents, such as domperidone, can enhance gastrointestinal motility.

④ Antibiotics, such as metronidazole and ciprofloxacin, can treat malabsorption caused by bacterial overgrowth.

⑤ Additionally, medications that promote blood circulation to remove stasis, dissolve fibrin, and improve affected blood vessels may also be selected.

⑥ In recent years, phototherapy, gamma interferon, autologous stem cell transplantation, and biologic agents have been reported to improve skin fibrosis and visceral involvement.

7 Prognosis

The prognosis of JSSc is better than that of adults, with a lower mortality rate; outcomes are closely linked to the extent of visceral organ involvement. The leading causes of death in JSSc are cardiac, renal, and pulmonary failure, while pericarditis, elevated serum creatinine, and pulmonary fibrosis often serve as significant predictors of mortality. More than 25% of patients die within the first year after diagnosis, and 73.3% succumb within five years. The 5‑year, 10‑year, and 15‑year survival rates for JSSc patients are 89%, 80%–87.4%, and 74%–87.4%, respectively—all markedly higher than those observed in adult patients. Studies have shown that a subset of JSSc patients experience rapid disease progression, with early onset of multiorgan failure, ultimately resulting in severe disability and death, whereas others follow a more indolent, insidious course, with lower mortality. Furthermore, mortality is not associated with the presence of autoantibodies, sex, or age at disease onset.

8 Summary

In summary, the etiology, pathogenesis, clinical features, diagnosis, and treatment of juvenile systemic sclerosis (JSSc) are similar to those in adults, yet they also exhibit distinct characteristics. However, JSSc is exceedingly rare in clinical practice; early cutaneous manifestations are often atypical, and visceral involvement tends to be mild. In the later stages, it frequently leads to disability or severe organ dysfunction. Therefore, patients presenting with early Raynaud phenomenon or abnormal skin changes at the fingertips should be given close attention, and routine assessment of multi‑system organ function is essential for early detection of disease, enabling timely diagnosis and treatment, and thereby reducing rates of disability and mortality.