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Progress in research on juvenile systemic scleroderma

10/09/2018

Juvenile system-ic scleroderma (JSSc), also known as juvenile systemic sclerosis, is a chronic connective tissue disease characterized by symmetrical skin thickening, sclerosis, and multiple organ fibrosis. It is rare in clinical practice, and lacks typical clinical manifestations and specific examination indicators in the early stage. It is easy to be misdiagnosed clinically, and early diagnosis and effective treatment are essential for improving prognosis. This article provides a brief review of the diagnostic criteria, epidemiology, etiology, pathogenesis, clinical manifestations, differentiation from adult SSc, treatment and prognosis of JSSc to enhance the understanding of JSSc and provide evidence for clinical diagnosis and treatment of JSSc.

1. Diagnostic criteria
The new JSSc diagnostic criteria were developed in 2007 by the European Association of Pediatric Rheumatology (PES), the American College of Rheumatology (ACR) and the European Union of Rheumatology (EULAR). The standard diagnoses patients who are younger than 16 years of age and meets 1 primary criterion and at least 2 secondary criteria as JSSc. This standard relates to the performance of the patient’s skin and internal organs and related positive indicators. In addition, the standard emphasizes the need for diagnosis of fingertip skin and finger joint involvement, whereas the diagnosis of SSc in adult SSc diagnostic criteria may be free of skin involvement. For sensitivity and specificity, this standard has been validated in adult SSc patients and requires long-term clinical validation in JSSc.

2. Epidemiology
Domestic and foreign literature reports that among all patients with scleroderma, the pre-16 years old accounted for less than 3%, JSSc is even rarer, and the prevalence rate is about 0.5/1 million. JSSc occurs in girls. The incidence rate of males and females is about 1:3. 6. The average age of onset is about 8 years old. The peak age of onset is between 10 and 16 years old. There is no clear racial bias and there is a certain family aggregation. JSSc often hides the onset, early symptoms are atypical, often misdiagnosed, ranging from onset to definite diagnosis, mostly in 1. 9 to 2. 8 years. In addition, the scleroderma that occurs in childhood has a high disability rate. 80% of the dysfunction caused by scleroderma in children reported in China is far higher than 11% to 44% reported by foreign countries. Scholars believe that It is related to the difference in the type of disease analyzed, the time of regular treatment, and whether or not to adhere to treatment.

3. Etiology and pathogenesis
The current cause of JSSc is still unclear, and its pathogenesis may involve the participation of multiple factors. It has been reported to be associated with autoimmune, vascular injury, heredity, infection, trauma, inflammation, and abnormal collagen metabolism.

3. 1 Autoimmune
High positive expression rate of antinuclear antibody (ANA) and various autoimmune-related antibodies such as anti-centromere antibody (ACA), anti-SCL-70 antibody, anti-PM-Scl antibody, anti-soluble antigen (ENA) in JSSc patients The positive detection rate of antibodies and the like in some patients suggests that autoimmunity plays an important role in its pathogenesis. Reiff et al compared the number of T lymphocytes in peripheral blood of adults with scleroderma and JSSc, and found that the number of resting regulatory T lymphocytes in JSSc patients decreased, and the expression of memory CD4 T lymphocytes increased. They hypothesized that the reduction of resting regulatory T lymphocytes and the increase in memory CD4 T lymphocytes initiate the onset of JSSc, suggesting a possible role for cellular immunity in JSSc.

3. 2 Vascular injury
Matucci-Cerinic et al reported that SSc is a disease that originates in blood vessels. Patients often suffer from damage to small blood vessels in the extremities, and there are Raynaud’s phenomenon and abnormal manifestations of extremity capillaries. When involving large blood vessels, it can cause severe skin ulcers and fingers. Or limb ischemic necrosis, and dysfunction of the heart, lungs, kidneys and gastrointestinal tract can occur. For most JSSc patients, the Raynaud’s phenomenon is also the first symptom, followed by peripheral microvascular dysfunction such as swelling of the fingers and abnormalities of the nails of the nails. Therefore, vascular injury is also an important factor in the pathogenesis of JSSc, possible mechanisms: 1 immune-mediated cytotoxicity, anti-endothelial antibodies, apoptosis of vascular endothelial cells induced by ischemia-reperfusion injury; 2 imbalance of vasoactive factors, including Increased production of vasoconstrictor endothelin and decreased production of vasodilator nitric oxide and prostacyclin. In patients with JSSc, a variety of pathogenic factors act on blood vessels, causing vascular damage, which is then remodeled in a fibrotic manner, leading to tissue ischemia, fibrosis, and multiple organ malfunctions.

3. 3 Other
JSSC is histopathologically characterized by excessive deposition of homogenized collagen fibers and inflammatory cells, similar to adult SSc patients, suggesting that inflammation and abnormal collagen metabolism are also involved in the pathogenesis of JSSc; a high family history may support genetic factors. The role in the pathogenesis, while the low incidence in twins suggests that genetic factors may be less or involve complex features of multiple genes; Denton et al reported that infection and trauma are associated with childhood scleroderma, possibly with immune activation In addition, the higher incidence of women indicates that the increased autoimmune tendency of estrogen and the inactivation of X-chromosome chimerism is considered to be another pathogenesis. However, the specific pathogenesis of JSSc needs further study.

4. Clinical manifestations
There are two main subtypes of JSSc: diffuse and apex. Diffuse JSSc patients with extensive skin involvement, characterized by progressive skin thickening and early involvement of internal organs such as the lungs, heart and kidneys, can be characterized by early swelling of the joints of the hands and feet, pain, and later skin sclerosis, accompanied by Renault Phenomenon, joint pain and movement disorders, tendonitis, myositis, bone changes, etc.; acral JSSc patients with localized and non-progressive skin thickening, sclerosis and peripheral vascular involvement, pulmonary arteries can occur High pressure or gastrointestinal malabsorption syndrome. The acral JSSc is characterized by vascular involvement, mainly manifested by Raynaud’s phenomenon, capillary abnormalities, fingertip depression, finger atrophy, calcareous, fingertip ischemic necrosis and ulceration. Patients with CREST syndrome performance are also considered to be of this type. In addition, approximately 27% of patients with JSSc exhibit features of other connective tissue diseases such as dermatomyositis or systemic lupus erythematosus, known as overlap syndrome. Related literature reports that 70% of JSSc patients have Raynaud’s phenomenon as the first symptom, 10% of them have ischemic necrosis at the fingertip; fingertip skin changes including edema and cirrhosis appear as the second most common symptom in 60% Patients; Raynaud’s phenomenon and skin sclerosis are the most common symptoms of JSSc throughout the course of the disease, affecting approximately 84% of patients, followed by 42% of patients with respiratory symptoms and 30% of those with gastrointestinal symptoms About 27% of those with arthritis, 15% of those with cardiac involvement, and renal phase, renal failure and central nervous system symptoms rarely occur, accounting for 3%, 5% and 0.7% respectively. .

5. Differences from adult SSc
The incidence of JSSc is about 3% to 10% of that of adults. Diffuse type is common, and adult SSc is limited by common type. JSSc early arthritis, myositis prevalence and Raynaud’s phenomenon are more serious than adults, and visceral involvement Significantly reduced, the difference between late and adult became less obvious; throughout the course of the disease, JSSc patients with interstitial pneumonia, renal crisis, gastroesophageal motility disorder, arterial hypertension, musculoskeletal symptoms are rarer than adults, cardiac involvement is more common than adults The involvement of other internal organs is similar to that of adults. In addition, the incidence of overlap syndrome in patients with JSSc is higher than in adults, and the positive rate of autoantibodies is lower. The overall mortality rate of patients with JSSc is lower than that of adults. Cardiac involvement is the most common cause of death. It is characterized by myocardial infarction, arrhythmia, congestive heart failure and cardiomyopathy. The main cause of death in adult SSc patients is pulmonary involvement. , manifested as interstitial lung disease and pulmonary hypertension.

6. Treatment
Because JSSc is unclear, there is no specific treatment, mainly anti-inflammatory, improved circulation, inhibition of immunity, anti-fibrosis and other symptomatic supportive treatment.

6. 1 Anti-inflammatory
Oral glucocorticoids reduce inflammation and are used in the treatment of active myositis, arthritis, and interstitial lung disease. Recommended dose: Prednisone 0. 3mg/(kg·d) ~ 0. 5mg/(kg·d), because the use of steroids may increase the risk of scleroderma kidney crisis, so blood pressure and kidney function must be closely monitored .

6. 2 Improve the cycle
Calcium channel blockers (CCB) can dilate blood vessels, relax vascular smooth muscle, reduce peripheral vascular resistance, improve circulation, and usually take oral nifedipine or nicardipine, which should be considered as first-line treatment of Raynaud’s phenomenon. Intravenous infusion of prostaglandins such as iloprost, a prostacyclin analogue, can dilate local blood vessels, inhibit inflammation, fight vascular remodeling, and treat severe Raynaud and fingertip ulcers. A recent study reported that intermittent infusion of iloprost is safe and effective in the treatment of refractory patients with Raynaud’s phenomenon and finger ulcers. Angiotensin-converting enzyme (ACE) inhibitors such as captopril and losartan can strongly dilate blood vessels and are thought to be effective in controlling blood pressure for a long time and stabilize renal function in JSSc patients. Should they be used to prevent hardening? The kidney disease of the skin disease is not completely clear. In addition, vascular-targeting agents, endothelin receptor antagonists (bosentan) and phosphodiesterase-5 inhibitors (sildenafil) can be used for the treatment of pulmonary hypertension, and bosentan can also prevent finger ulcers. But can not interfere with the fibrosis of the lungs.

6. 3 Inhibition of immunity
Cyclophosphamide is currently controversial, and despite its known toxicity and unmet long-term effects, most scholars still recommend treatment for JSSc patients with interstitial lung disease. The amount of intravenous shock therapy: 0. 5 ~ 1 g / m2 per month, for at least 6 months, in order to prevent cystitis, we must emphasize adequate hydration and frequent urination, prevention with mesna sodium (sodium sulfonate) It can reduce the damage of the bladder mucosa. Methotrexate is widely used in the treatment of many connective tissue diseases and can improve the skin symptoms of diffuse scleroderma in early adults. It is currently believed that methotrexate can be used to treat JSSc, especially in the early stages of diffuse patients. Subcutaneous injection of methotrexate 15 mg/m2 per day is an option for the first treatment in children. It can be treated with mycophenolate 1 500 mg/(m2·d) according to the progress of the disease to enhance the efficacy.

6. 4 Anti-fibrosis
Penicillamine can inhibit collagen cross-linking, inhibit the synthesis of new collagen, and reduce skin sclerosis. Children’s dosage: 3mg/(kg·d) in the first 2 months, and increase to the maximum dose in 2mg/(kg·d) in the future. 15mg / (kg·d).
6. 5 Other
1).Physical therapy such as massage and hyperthermia can promote microcirculation and improve skin symptoms;
2).proton pump inhibitors (PPI), such as omeprazole and lansoprazole, can prevent gastroesophageal reflux disease and esophageal ulcers;
3).promote gastrointestinal motility drugs, such as domperidone, can promote the movement of the gastrointestinal tract;
4).antibiotics, such as metronidazole, ciprofloxacin, can treat malabsorption caused by excessive bacterial growth;
5).In addition, you can choose drugs that promote blood circulation, dissolve fibrinolytic proteins, and improve diseased blood vessels;
6).In recent years, photochemotherapy, γ-interferon, autologous stem cell transplantation, and biological agents have been reported to improve skin hardening and visceral involvement.

7. Prognosis
The prognosis of JSSc is better than that of adults, and the mortality rate is low. The prognosis is related to the damage of internal organs. The main cause of JSSc death is heart, kidney, lung function failure, pericarditis, increased serum creatinine, and fibrosis in the lungs are often important predictors of death. More than 25% of JSSc patients died in the first year after diagnosis, and 73.3% of patients developed 5 years after diagnosis. The 5-year, 10-year, and 15-year survival rates of JSSc patients were 89%, 80% to 87. 4%, and 74% to 87. 4%, respectively, which were significantly higher than those in adults. The study found that a small number of patients in JSSc developed rapidly and developed visceral organ failure in the early stages, which eventually led to severe disability and death, while other patients experienced a slow and hidden disease with a lower mortality rate. In addition, mortality is independent of autoantibodies, gender, and age at onset.

8. Summary
In summary, the etiology, pathogenesis, clinical features, diagnosis and treatment of JSSc are similar to those of adults and have their own characteristics. However, JSSc is very rare in the clinic. The early skin symptoms are atypical, and the symptoms of visceral damage are mild. In the later stage, the patient often causes disability or severe visceral dysfunction. Therefore, patients with early Raynaud’s phenomenon or abnormal skin changes should be given enough attention. Regular examination of organ function in various systems will help early detection of lesions, early diagnosis and treatment, and reduce morbidity and mortality.

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