Application of integrated traditional Chinese and Western medicine in the treatment of juvenile localized scleroderma with skin ulcer: a case report

Background: Juvenile Localized Scleroderma (JLS) is a rare pediatric rheumatic disease characterized by inflammation and skin sclerosis. The side effect of consensus-recommended medications and the risk of disability posed challenges to the JLS treatment. We intend to demonstrate the potential of traditional Chinese medicine in treating JLS with skin ulcers and reducing the dose of glucocorticoid. Method: Here we report a case of a 13-year-old male with JLS who took oral methotrexate tablets of 10 mg/week and methylprednisolone of 6 mg/day for over six months without significant effect and suffered from skin ulcers on the dorsal feet one month after drug cessation. Subsequently, the patient was treated with integrated traditional Chinese and Western medicine of low-dose glucocorticosteroid, adjusted Shenqi Huoxue formula and Jinshe Xiaoyan formula, etc. Results: After integrated treatment, the patient’s dorsal feet ulcers healed and the skin sclerosis and hyperpigmentation improved significantly. Conclusions: This case report suggests that integrated traditional Chinese and Western medicine can be used as an effective treatment for JLS.


Background
Juvenile localized scleroderma (JLS) is a rare pediatric disease of inflammatory sclerotic skin invasion without visceral damage, typically affecting the dermis and occasionally the subcutaneous fat and fascia [1]. Inflammation and microvascular damage may cause local ischemia and hypoxia, resulting in chronic skin ulcers [2,3]. The skin sclerosis surrounding the ulcer makes it less likely to heal. Additionally, open wounds are susceptible to bacterial contamination, leading to the formation of a biofilm that inhibits the regeneration of the wound epithelium, causing delayed healing [4]. Consequently, JLS with skin ulcers is hard to treat and generally has a poor prognosis.
Over the years, many treatments have been tried for JLS with a limited significant evidence base. The consensus of JLS management recommends systemic corticosteroids in association with methotrexate (MTX) [5]. However, long-term use of the two drugs potentially causes multiple side effects [6,7], such as osteoporosis, gastrointestinal disease and growth suppression, causing parental apprehension and resistance. Thus, it is challenging to individualize the treatment, balance drug efficacy with side effects, control the disease progression to avoid disability and ameliorate psychological problems based on consensus-recommended medications. Traditional Chinese medicine (TCM) provides individualized treatment based on the holistic concept and pattern differentiation. Specialist physicians in China tend to use integrated traditional Chinese and Western medicine treatment, especially for severe refractory JLS, which is considered more effective than chemical-drug-only-regimens [8].
In this case report, a patient with JLS combined with skin ulcers showed healing of ulcers and improvement of hyperpigmentation after using the integrated treatment of low-dose glucocorticosteroid, adjusted Shenqi Huoxue formula and Jinshe Xiaoyan formula, etc.

Case description
The patient has signed the informed consent form. In October 2014, a 13-year-old male patient visited the local hospital for small patches of hyperpigmentation and sclerosis on the left abdomen, undiagnosed and unmedicated. In June 2016, he was affected by patchy and linear sclerotic spots on the face and extremities. Thereupon, he was diagnosed with JLS according to the skin biopsy report which showed "scleroderma, superficial dermal collagen also seen homogenized", and received oral MTX 10 mg weekly and methylprednisolone 6 mg per day for over six months without significant effect. Thus, his parents decided to discontinue the drugs. However, one month after drug cessation, he suffered from skin ulcers on the dorsal feet with a gradually expanding area, significant pain and difficulty walking.
On August 5, 2017, he presented to our hospital for integrated treatment. His physical examination showed: hyperpigmentation and sclerosis on the lateral margins of both eyes, the trunk and the lower extremities; skin ulcers covered with scabs on the dorsal feet; and stiffness of the ankle, metatarsophalangeal and interphalangeal joints. The laboratory examination outcomes indicated elevated inflammatory markers (Table 1). Chest CT and echocardiography and other relevant tests were done to exclude visceral damages.
In terms of TCM, he was diagnosed with "dermatosclerosis with heat-toxin complicated by stasis" [9] based on the four-diagnosis-he had a red complexion, halitosis, dry stools, yellow urine, poor sleeping, dark red tongue, thin yellow coating and rapid pulse.
During his treatment in our hospital, from August 2017 to March 2018, the treatment regimen was as follows. Oral Jixuegan tablets, Fukang capsule, modified Shenqi Huoxue formula and Jinshe Xiaoyan formula (Table 2), intravenous Breviscapine injection and topical fumigation Shenqi Huoxue formula were given for TCM treatment. Besides, oral methylprednisolone 8 mg per day, topical metronidazole and gentamicin, and intravenous Bozhi Glycopeptide injection were given for chemotherapeutic treatment. After his second discharge, the methylprednisolone dosage was reduced to 4 mg per day. A quarterly outpatient follow-up was conducted and TCM prescriptions were modified according to the patient's recent symptoms. Remarkably, no other concomitant treatment, such as topical agents and surgical wound debridement, has been performed.
After two hospitalizations, we observed that the dorsal foot ulcer healed (Figure 1), the LoSCAT Scores reduced (Table 3, 4), and the joints range increase. Besides, there were no adverse events reported by the patient and observed by the medical professionals. The timeline of the patient's medical history is shown in Figure 2.

Discussion
JLS is a rare pediatric disease characterized by excessive collagen production and increased extracellular matrix deposition [10]. Complications of skin ulcers are triggered by tissue ischemia, which generates oxygen-free radicals that damage the skin [11]. Repetitive vasospasm causing reperfusion injury can further impair tissue viability and lead to unhealing wounds [12]. The prevalence of JLS Table 1 The laboratory examinations outcomes during the treatment Reference values: red blood cell: (4.09-5.74) × 10 12 /L; white blood cell: (3.97-9.15) × 10 9 /L; hemoglobin: (131-172) g/L; blood platelets: (100-300) × 10 9 /L; erythrocyte sedimentation rate: 0-20 mm/h; immunoglobulin G: (7.0-16.6) g/L; interleukin-1β: < 5 pg/mL; interleukin-2: (223-710) U/mL; interleukin-4: (0.0-80.0) pg/mL; interleukin-6: < 6.4 pg/mL; interleukin-8: (0.00-62.00) pg/mL; interleukin-10: (0.0-9.1) pg/mL; bone mineral density (Z value): 2-(-2).    The with hard-to-heal lower extremity ulcers is relatively low (4% of the scleroderma population) [13]; however, these ulcers can cause pain, infection, amputation and sepsis, seriously hampering the patients' life quality. The inflammatory phase is crucial during wound healing, and overexpression of inflammatory factors is detrimental to the healing of skin ulcers [14]. In this case, the patient had mixed scleroderma, a combination of circumscribed scleroderma, linear scleroderma and pansclerotic scleroderma, of which pansclerotic scleroderma is the most severe form and can lead to skin ulceration [15,16]. He suffered from a dorsal feet ulcer for more than six months, which may be related to the abnormal elevation of his IL-1, IL-2, IL-6, and IL-8. As such, the primary treating target of is to suppress inflammation and prevent fibrosis progression in order to reduce tissue damage. Despite the consensus of pediatric experts on the use of MTX and corticosteroids for the treatment of JLS [17], approximately a third of patients have an inadequate response to them [18]. Thus, it is necessary to evaluate the potential alternative treatments for JLS. In this case, the patient received undesirable effect of MTX and methylprednisolone treatment after six months when a response is normally expected [19]. Thus, his parents opt to change the treatment regimen. We used a relatively small dose of methylprednisolone integrated with TCM. After nine days, the patient's left dorsal foot ulcer tended to heal. After eight months, the LoSAI score decreased from 47 to 12, the LoSDI score decreased from 62 to 43, the dorsal feet ulcer healed, the general skin hyperpigmentation improved, and the immunoglobulin and interleukin series returned to normal. Besides, range of motion of joints improved and there was no organ damage. Such response was very impressive, especially at the speed of response and control of disease course, and this might not be realized by small doses of glucocorticoids alone. This suggests that integrated treatment can effectively inhibit excessive inflammatory cytokines and turn wound healing from the inflammatory phase into the repair phase.
TCM has been applied to JLS treatment with promising outcomes in many hospitals in China. Clinical and modern pharmacological studies have demonstrated that TCM can act on various pathways to exert anti-inflammatory, anti-fibrotic, and blood circulation-improving effects. In this case, Shenqi Huoxue formula and Jinshe Xiaoyan formula which have been applied in clinic for years were prescribed according to the TCM theory and our clinical experiences. Among the compositions of the two formulas, Astragali Radix can inhibit collagen production through the TGF-β/SMAD pathway for anti-fibrotic effect [20], and its 2:1 combination with Rehmanniae Radix can enhance the migration of fibroblasts and promote wound healing [21]. Salviae Miltiorrhizae Radix et Rhizoma can improve microcirculation and promote wound healing by enhancing tissue perfusion and neointima formation [22]. As well, it has anti-inflammatory [23] and anti-fibrotic effects [24]. Cynanversicoside A and cynanversicoside C in Cynanchi Paniculati Radix et Rhizoma can reduce IL-6 and IL-1 levels in vivo by regulating NF-ĸB and MAPK pathways [25]. Topical fumigation Shenqi Huoxue formula can improve peripheral blood circulation and promote terminal necrotic ulcer healing [26].

Conclusion
This case report seeks to demonstrate the potential of TCM in treating JLS and reducing the dose of glucocorticoid in the absence of evidence base. Further basic studies and higher evidence such as multicenter randomized controlled trials or real-world studies are needed to explore the mechanism of Chinese medicine and its synergistic effects with chemotherapy, and to support the JLS TCM treatment in the future.