Abstract
目的
回顾嗜酸性筋膜炎（EF）的临床症状、化验、检查、治疗及预后，并探讨超声在EF中的应用价值。
方法
回顾2006年1月1日~2022年2月28日在我中心就诊的EF患者的临床资料，并进行统计描述、分析，评估超声及磁共振成像（MRI）结果间的一致性。
结果
45例EF患者，男女比例3.5:1，发病年龄16~64岁，平均病程22.6个月，从出现症状到确诊的平均时间为16个月。最常见的诱因是剧烈运动诱发，占22%（10/45例）。EF以对称性四肢受累为主，前臂（86.7%）及小腿（80%）最常见。临床表现包括：皮下肿胀/紧硬（95.6%）、关节痛/炎（55.6%）、沟征（42.2%）、手关节屈曲挛缩（42.2%）、色素沉着（37.8%）、橘皮样皮肤病变（13.3%）等。31例（68.9%）患者嗜酸性粒细胞升高，52.3%（23/44例）的患者IgG升高，9例（20%）抗核抗体阳性。21例患者接受了≥200 mg/d（3~5 d）的大剂量激素治疗，与未接受大剂量激素治疗的患者相比，虽未达到统计学差异，但患者入院前曾复发的比例更高、受累部位更广、IgG升高的比例更多，且没有发热。共有31例（68.9%）患者完成了随访，12/31例（38.7%）患者完全缓解，随访的中位时间为3.2年（0.2~15.9年），5.5年时完全缓解的累积发生率为44.1%。未发现与治疗反应相关的特殊基线特征及免疫抑制剂种类。共26例患者同时进行了超声及MRI检查，超声与MRI在确定筋膜增厚/炎症方面一致性很好（Kappa=0.91）。
结论
EF的临床特征为对称性四肢皮下肿胀、紧硬，伴嗜酸性粒细胞、IgG升高，激素治疗效果好。超声识别皮下筋膜增厚是诊断EF的一个早期最有效的工具。
Keywords: 嗜酸性粒细胞增多, 筋膜炎, 超声, 糖皮质激素
Abstract
Objective
To evaluate the clinical features, laboratory and imaging results, treatment and outcomes of eosinophilic fasciitis (EF) and assess the value of ultrasound in the diagnosis of EF.
Methods
We retrospectively analyzed the clinical data of 45 patients with EF treated in our center from January 1, 2006 to February 28, 2022. The consistency between the diagnoses of EF based on ultrasound and MRI findings was assessed.
Results
In the 45 EF patients (male/female ratio 3.5:1), the age of onset ranged from 16 to 64 years with a mean disease course of 22.6 months. The average time from symptom onset to diagnosis was 16 months. The most common possible trigger of the disease was vigorous exercise (10/45), causing symmetrical lesions in the limbs, most commonly in the forearms (86.7%) and lower legs (80%). Clinical features of EF included subcutaneous swelling and induration (95.6%), arthralgia and arthritis (55.6%), groove sign (42.2%), hand joint contractures (42.2%), skin pigmentation (37.8%), and peau d'orange appearance (13.3%). Eosinophilia was found in 31 patients (68.9%). Hypergammaglobulinemia was seen in 23/44 (52.3%) and positive antinuclear antibodies in 9 (20%) of the patients. Twentyone of the patients were treated with high-dose methylprednisolone (≥200 mg daily for 3 to 5 consecutive days), and compared with the patients who did not receive this treatment, these patients more frequently experienced relapse before admission, had more extensive involvement, and had a higher rate of hypergammaglobulinemia without fever, but these differences were not statistically significant. Of the 31 patients (68.9%) with follow-up data (for a median of 3.2 years [range 0.2-15.9]), complete remission was achieved in 12 (38.7%) patients, and the accumulative complete remission rate was 44.1% at 5.5 years. No specific baseline characteristics or immunosuppressants were found to correlate with the treatment response. A total of 26 patients underwent both ultrasound and MRI examination, and the Kappa value of the diagnostic results between ultrasound and MRI was 0.91.
Conclusion
EF is characterized by symmetrical subcutaneous swelling and induration in the limbs, accompanied by eosinophilia and hypergammaglobulinemia. Glucocorticoid is effective for treating EF. Ultrasound examination can identify thickening of subcutaneous fascia for an early diagnosis of EF.
Keywords: eosinophilia, fasciitis, ultrasound, glucocorticoids
嗜酸性筋膜炎（EF）是一种罕见疾病，1975年Shulman首次对该病进行了描述[1]，因此又称Shulman综合征。EF的病因尚不明确，发现的相关因素包括剧烈运动、感染、外伤、药物治疗、自身免疫性疾病及肿瘤等[2-4]。患者的皮肤早期出现非凹陷性水肿，随着病情进展，肿胀消退，出现皮下筋膜的增厚，皮肤硬化，伴有褶皱，呈“橘皮样外观” [5]。抬高受累肢体时，沿浅表静脉走行出现可见的沟回（“沟征”）[6]。患者多有嗜酸性粒细胞升高，典型的病理表现为增厚的筋膜内炎性细胞和嗜酸性粒细胞浸润，磁共振成像（MRI）检查发现皮下浅筋膜及深筋膜T2信号增强，其他影像检查如超声及PET/CT也有助于评估皮肤及筋膜情况[7, 8]。高频超声因其安全、快速、无创等优势，在风湿病的诊断及随访中的应用越加广泛。Pousa-Martinez等[9]发现1例EF患者超声下筋膜厚度为2.5 mm，而10名健康对照组的筋膜厚度为0.4~0.6 mm。近期亦有少量个案及病例系列报道[10, 11]发现EF患者的皮下超声显示筋膜增厚，提示超声发现皮下筋膜增厚对于诊断EF有潜在的价值。目前尚缺乏大样本的研究来评估超声对EF的诊断及随访价值。
目前EF尚没有公认的诊断标准，主要依靠临床和实验室结果，结合活检或影像学来进行诊断。治疗仍是一个挑战，糖皮质激素（MP）对多数患者有效，对于激素疗效不佳或复发的患者，可考虑加用免疫抑制剂治疗，如甲氨蝶呤、环磷酰胺等，也有肿瘤坏死因子抑制剂、白介素6（IL-6）抑制剂、Janus激酶（JAK）抑制剂治疗有效的报道[12-14]。本研究的目的是回顾性分析本中心收治的EF患者，描述EF的临床特征、治疗及预后，初步评估超声在EF中的应用价值及治疗方法的探讨。
1. 资料和方法
1.1. 研究对象
检索2006年1月1日~2022年2月28日在我中心就诊的EF患者的病历，EF的诊断基于患者的临床症状、化验结果、影像学检查及活检。排除系统性硬化症、移植物抗宿主病或放射性皮肤纤维化的患者。所有实验均通过中国人民解放军总医院伦理委员会审批（S2022-429-01）。
1.2. 临床资料
收集所有患者的一般人口学资料、临床特征、实验室、影像学、组织病理学结果及治疗情况。基线变量包括年龄、性别、病程、诱因、合并症、相关体检结果和受累部位：头颈部、躯干、上肢（上臂、前臂、腕关节以远）和下肢（大腿、小腿、踝关节以远）。记录橘皮样皮肤表现（皮肤不规则凹陷、皱褶、橘皮样外观）和沟征。收集实验室结果，包括：血常规、外周血嗜酸性粒细胞计数及升高情况（升高定义为计数≥0.5×109/L或比例≥5%）、血沉（ESR）、C反应蛋白（CRP）、肌酸激酶、补体、免疫球蛋白、自身抗体等。收集影像学检查结果，包括：肌电图、MRI结果（皮肤增厚/炎症、筋膜增厚/炎症、肌肉炎症）、超声检查结果（筋膜增厚定义为>1 mm）。记录患者活检病理结果及嗜酸性粒细胞浸润情况。记录患者治疗药物，包括糖皮质激素、免疫抑制剂、生物制剂等。对所有患者进行随访，治疗反应定义为：完全缓解（肿胀、紧硬等症状消失，无关节屈曲挛缩，停用MP且指标正常：CRP、ESR及嗜酸性粒细胞计数），部分缓解（肿胀、紧硬等症状改善，有/无关节屈曲挛缩，指标较基线好转，未停用MP），无改善（症状及指标无改善或者恶化）。
1.3. 统计学方法
采用SPSS19.0软件进行统计描述及分析。定量资料的描述采用均数±标准差、中位数（范围），统计分析采用t检验或秩和检验，定性资料的描述采用率或构成比，统计分析采用χ2检验或Fisher's，用Kaplan-Meier方法评估完全缓解的累积发生率，用校正了年龄和性别的Cox回归模型分析基线特征与治疗反应之间的潜在关联，评估超声及MRI结果间的一致性（Kappa值），检验水准α=0.05。
2. 结果
2.1. 一般资料
共入组45例EF患者，男女比例3.5:1，发病时平均年龄35.4（16~64）岁（表 1）。从出现症状到确诊的中位时间为6个月，平均16.0（0~279）个月，到本中心就诊时平均病程22.6（2~279）个月。患者的发病诱因包括：剧烈运动（10例）、感染（1例上呼吸道感染）、药物（3例，其中1例在接种新冠疫苗后出现症状）、外伤（1例）。5例（11.1%）合并自身免疫性疾病，包括脊柱关节炎、银屑病关节炎、原发性胆汁性胆管炎、IgA肾病及结缔组织病各1例，3例（6.7%）硬斑病，7例（15.6%）淀粉样病变，1例肿瘤（直肠癌），1例嗜酸性粒细胞性肺炎，5例（11.1%）有雷诺现象。
1.
嗜酸性筋膜炎患者的特征
Characteristics of the patients with eosinophilic fasciitis
| Characteristic | Total patients (n=45) | Follow-up patients (n=31) |
| SD: Standard deviation; BMI: Body mass index; CRP: C- reactive protein; ESR: Erythrocyte sedimentation rate; IgG: Immunoglobulin G; ANA: Antinuclear antibodies; EMG: Electromyologram; MRI: Magnetic resonance imaging. | ||
| Gender (male) | 35 (77.8%) | 24 (77.4%) |
| Age at onset (Mean±SD, range) | 35.4 (12.7), 16-64 | 33.9 (11.1), 16-57 |
| Course of disease (month, Mean±SD, range) | 22.6 (45.7), 2-279 | 22.3 (48.8), 2-279 |
| Time from symptom onset to diagnosis (month, Mean±SD, range) | 16.0 (41.6), 0-279 | 19.1 (49.3), 0-279 |
| BMI (Mean±SD) | 24.1 (3.1) | 24.1 (3.5) |
| Vigorous exercise | 10 (22.2%) | 7 (22.6%) |
| Infection | 1 (2.2%) | 0 (0) |
| Medication | 3 (6.7%) | 2 (6.5%) |
| Trauma | 1 (2.2%) | 1 (3.2%) |
| Autoimmune diseases | 5 (11.1%) | 5 (16.1%) |
| Amyloidosis | 7 (15.6%) | 4 (12.9%) |
| Raynaud's phenomenon | 5 (11.1%) | 4 (12.9%) |
| Fever | 3 (6.7%) | 2 (6.5%) |
| Fatigue | 3 (6.7%) | 1 (9.7%) |
| Myalgia | 9 (20%) | 7 (22.6%) |
| Myasthenia | 1 (2.2%) | 1 (3.2%) |
| Arthralgia/arthritis | 25 (55.6%) | 18 (58.1%) |
| Numbness | 11 (24.4%) | 7 (22.6%) |
| Peau d'orange | 6 (13.3%) | 4 (12.9%) |
| Groove sign | 19 (42.2%) | 13 (41.9%) |
| Joint contractures of the hands | 19 (42.2%) | 13 (41.9%) |
| Tight skin | 17 (37.8%) | 11 (35.5%) |
| Subcutaneous swelling/induration | 43 (95.6%) | 29 (93.5%) |
| Skin pigmentation | 17 (37.8%) | 12 (38.7%) |
| Skin depigmentation | 2 (4.4%) | 2 (6.5%) |
| Subcutaneous nodule/mass | 2 (4.4%) | 1 (3.2%) |
| Elevated CRP (≥8 mg/L) | 17/44 (38.6%) | 13 (41.9%) |
| Elevated ESR (≥20 mm/h) | 11/44 (25.0%) | 8 (25.8%) |
| Eosinophilia (≥0.5×109/L or ≥5% of total leukocytes) | 31 (68.9%) | 21 (67.7%) |
| IgG > 1.6 g/dL | 23/44 (52.3%) | 15/30 (50%) |
| Elevated ANA (titer ≥1:320) | 9 (20%) | 6 (19.4%) |
| EMG abnormalities | 4/9 (44.4%) | 2/6 (33.3%) |
| MRI shows fascial thickening/inflammation | 30/30 (100%) | 19/19 (100%) |
| MRI shows skin thickening/inflammation | 4/30 (13.3%) | 4/19 (21.1%) |
| MRI shows muscle inflammation | 11/30 (36.7%) | 10/19 (52.6%) |
2.2. 症状及体征
患者有发热、疲乏、肌痛、肌无力等症状（表 1）。25例（55.6%）患者有关节痛/炎，涉及肩关节（10例，22.2%），肘关节（6例，13.3%），腕关节（15例，33.3%），手指关节（7例，15.6%），髋关节（2例，4.4%），膝关节（9例，20%），踝关节（13例，28.9%）及足趾关节（4例，8.9%）。11例（24.4%）出现受累肢体麻木，其中2例有腕管综合征。在6例（13.3%）患者中观察到橘皮样皮肤病变，19例（42.2%）沟征，19例（42.2%）出现手关节屈曲挛缩（“祈祷征”）。17例（37.8%）查体发现皮肤紧硬，43例（95.6%）有皮下肿胀/紧硬，17例（37.8%）出现皮肤色素沉着。
EF以对称性四肢受累为主，仅1例患者为单侧受累（左侧小腿）。上肢受累41例（91.1%），下肢受累40例（88.9%），仅上肢受累3例（6.7%），仅下肢受累4例（8.9%）。前臂是最常见受累的部位（86.7%），其次是小腿（80%）（表 2）。有2例患者出现双手手指肿胀。1例患者出现颜面部的肿胀紧硬，该患者经系统评估后排除系统性硬化症。
2.
嗜酸性筋膜炎患者的受累部位
Affected sites in patients with eosinophilic fasciitis
| Affected sites | Total patients (n=45) | Follow-up patients (n=31) |
| Head and neck | 3 (6.7%) | 2 (6.5%) |
| Trunk | 8 (17.8%) | 4 (12.9%) |
| Right upper arm | 6 (13.3%) | 4 (12.9%) |
| Right forearm | 39 (86.7%) | 27 (87.1%) |
| Distal of right wrist | 20 (44.4%) | 14 (45.2%) |
| Right thigh | 13 (28.9%) | 8 (25.8%) |
| Right lower leg | 36 (80%) | 25 (80.6%) |
| Distal of right ankle joint | 4 (8.9%) | 3 (9.7%) |
| Left upper arm | 8 (17.8%) | 5 (16.1%) |
| Left forearm | 39 (86.7%) | 27 (87.1%) |
| Distal of left wrist | 21 (46.7%) | 15 (48.4%) |
| Left thigh | 13 (28.9%) | 8 (25.8%) |
| Left lower leg | 36 (80%) | 25 (80.6%) |
| Distal of left ankle joint | 4 (8.9%) | 3 (9.7%) |
2.3. 化验及检查
31例（68.9%）有嗜酸性粒细胞升高，17/44例（38.6%）CRP升高，11/44例（25.0%）ESR升高。7例（15.6%）患者有贫血，16例（35.6%）血小板升高，23/44例（52.3%）IgG升高（表 1、3）。9例患者发现抗核抗体阳性（ANA≥1:320）（其中有1例原发性胆汁性胆管炎、1例结缔组织病、1例硬斑病合并IgA肾病），RF阳性4例，抗Smith抗体、抗着丝点抗体、R0-52抗体、抗线粒体抗体及抗线粒体抗体-M2阳性各1例。
3.
嗜酸性筋膜炎患者的实验室结果
Laboratory results of the patients with eosinophilic fasciitis
| Laboratory results | Total patients (n=45) |
| Abbreviations: SD: Standard deviation; CRP: C- reactive protein; ESR: Erythrocyte sedimentation rate; IgA: Immunoglobulin A; IgE: Immunoglobulin E; IgM: Immunoglobulin M. | |
| Anemia | 7 (15.6%) |
| Leukocytosis | 6 (13.3%) |
| Thrombocytosis | 16 (35.6%) |
| Thrombocytopenia | 1 (2.2%) |
| Eosinophil, Mean±SD, range, 109/L | 0.7 (0.6), 0-2.17 |
| CRP, Mean±SD, range, mg/L | 9.2 (10.1), 0.5-52.1 |
| ESR, Mean±SD, range, mm/h | 15.4 (19.8), 1-100 |
| Hypoalbuminemia | 6 (13.3%) |
| Elevated creatinine | 1 (2.2%) |
| Elevated creatine kinase | 1 (2.2%) |
| Elevated lactate dehydrogenase | 2 (4.4%) |
| Elevated IgA | 5/44 (11.4%) |
| Elevated IgE | 8/44 (18.2%) |
| Elevated IgM | 5/44 (11.4%) |
| Low complement C3 | 4/44 (9.0%) |
| Low complement C4 | 2/44 (4.5%) |
30例患者至少做了1个部位的肌肉MRI。共46例次MRI，包括腰背（3例）、上臂（6例）、前臂（18例）、手（3例）、大腿（3例）、小腿（12例）、足（1例），46例次MRI均有筋膜增厚/炎症，4/46例有皮肤增厚/炎症，13/46例有肌肉炎症。
5例患者进行了PET/CT检查，2例提示软组织代谢增高。4/9例患者肌电图异常，均提示神经源性受损，包括2例周围神经受损、1例双侧正中神经受损、1例右胫前肌、右外展拇短肌、左股四头肌、左三角肌神经源性损害。15例患者完善了骨髓涂片及活检，5/15例有骨髓嗜酸性粒细胞比例升高（比例7.6%~16%）。23/28例患者皮肤软组织活检阳性，4/28例患者的组织病理有嗜酸性粒细胞增多。7/28例组织病理刚果红染色阳性，其中3/7例患者的腹壁脂肪病理同样有刚果红染色阳性，5/7例患者（包含3例腹壁病理阳性）完善了骨髓涂片及活检，均未发现血液病肿瘤证据。
2.4. 治疗
16例患者入院前有疾病复发，包括停用激素（8例）及激素减量（8例），减量的患者复发前激素用量平均为12.5（5~30 mg）mg/d。所有患者均接受了糖皮质激素治疗，平均剂量36.9 mg/d，平均0.5 mg/kg·d。有21例患者接受了大剂量激素治疗（≥200 mg/d，连续3~5 d），与未接受大剂量激素的患者相比，前臂受累比例更高（分别为100%及75%，P=0.04）。虽未达到统计学差异，但大剂量激素组的患者入院前复发的比例更高、累积受累部位更多、IgG升高的比例更多，且没有发热（表 4）。
4.
不同剂量激素治疗的患者的特征比较
Comparison of characteristics of the patients treated with different doses of glucocorticoids
| Item | GC≥200 mg (n=21) | GC < 200 mg (n=24) | P |
| GC: Glucocorticoids; mid: Median; IgG: Immunoglobulin G; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate. | |||
| Relapse before admission | 10 (47.6%) | 6 (25%) | 0.11 |
| Fever | 0 (0) | 3 (12.5%) | 0.28 |
| Subcutaneous swelling/induration | 21 (100%) | 22 (91.7%) | 0.53 |
| Head and neck | 0 (0) | 3 (12.5%) | 0.28 |
| Trunk | 2 (9.5%) | 6 (25%) | 0.33 |
| Right upper arm | 5 (23.8%) | 1 (4.2%) | 0.14 |
| Left upper arm | 4 (19.0%) | 4 (16.7%) | 1.00 |
| Left /Right forearm | 21 (100%) | 18 (75%) | 0.04 |
| Distal of right wrist | 11 (52.4%) | 9 (37.5%) | 0.32 |
| Distal of left wrist | 11 (52.4%) | 10 (41.7%) | 0.47 |
| Left/Right thigh | 8 (38.1%) | 5 (20.8%) | 0.20 |
| Left/Right lower leg | 17 (81.0%) | 19 (79.2%) | 1.00 |
| Distal of left/right ankle joint | 3 (14.3%) | 1 (4.2%) | 0.51 |
| Cumulative affected sites, mid, range | 6 (4-12) | 5 (1-8) | 0.13 |
| Eosinophilia | 12 (57.1%) | 13 (54.2%) | 0.84 |
| Elevated IgG | 13 (61.9%) | 10 (41.7%) | 0.22 |
| Elevated CRP | 8 (38.1%) | 9 (37.5%) | 0.94 |
| Elevated ESR | 6 (28.6%) | 5 (20.8) | 0.60 |
| Course of disease [month, median (range)] | 7 (3-279) | 15 (2-151) | 0.39 |
| Time from symptom onset to diagnosis [month, median (range)] | 6 (0-279) | 6.5 (0-53) | 0.46 |
未有患者接受激素单药治疗。39例患者接受激素和至少1种免疫抑制剂治疗，包括环磷酰胺（2例），来氟米特（24例），甲氨蝶呤（8例），吗替麦考酚酯（6例），硫唑嘌呤（3例）。9例患者加用青霉胺，23例加用硫酸羟氯喹，1例加用秋水仙碱，2例加用沙利度胺，1例加用白芍总苷。1例患者接受了巴瑞替尼单药治疗。
2.5. 随访
共有31例（68.9%）患者完成了随访，12/31例（38.7%）患者完全缓解，随访中位时间3.2年（0.2~15.9年），Kaplan-Meier生存分析显示：5.5年时完全缓解的累积发生率为44.1%（图 1）。共20/31例（64.5%）患者停用激素，停药的中位时间为41个月（2~167个月），其中部分缓解6/17例（35.3%），未改善2/2例（100%）。有17例患者在随访时停用了所有药物，其中完全缓解10例，部分缓解5例，未改善2例。剩余2例完全缓解的患者仅接受硫酸羟氯喹治疗。2例患者在随访期间出现硬斑病，其中1例基线时抗核抗体阳性。4例合并有淀粉样病变的随访患者均未达到完全缓解。没有发现单一的免疫抑制剂与治疗后完全缓解相关（表 5）。未发现与完全缓解相关的危险因素（表 6）。
1.
完全缓解的累积发生率
Cumulative incidence of complete response.
5.
31例随访患者的治疗与疾病完全缓解/部分缓解之间的关系
Association between the treatments and complete/partial response among the 31 patients with follow-up data
| Item | Complete response | Complete or partial response | |||
| HRa (95% CI) | P | HRa (95% CI) | P | ||
| CTX: Cyclophosphamide; LEF: Leflunomide; MMF: Mycophenolate mofetil; AZA: Azathioprine; MTX: Methotrexate; HCQ: Hydroxychloroquine sulfate. aAdjusted for age and gender. | |||||
| Treatment at baseline | |||||
| CTX | 2.03 (0.22-18.46) | 0.53 | 1.44 (0.31-6.77) | 0.65 | |
| LEF | 0.46 (0.14-1.54) | 0.21 | 0.65 (0.29-1.43) | 0.28 | |
| MMF | 0.85 (0.18-4.04) | 0.84 | 0.95 (0.35-2.54) | 0.91 | |
| AZA | 4.45 (0.76-26.00) | 0.10 | 1.94 (0.41-9.13) | 0.40 | |
| MTX | 0.88 (0.18-4.43) | 0.88 | 1.20 (0.43-3.34) | 0.72 | |
| HCQ | 0.92 (0.29-2.96) | 0.89 | 1.41 (0.64-3.11) | 0.40 | |
| Treatment during follow-up | |||||
| LEF | 0 | 0.99 | 2.05 (0.58-7.25) | 0.27 | |
| MMF | 0 | 0.99 | 2.14 (0.60-7.65) | 0.24 | |
| AZA | 0 | 0.99 | 1.28 (0.15-11.14) | 0.82 | |
| MTX | 0 | 0.99 | 12.64 (1.13-141.73) | 0.04 | |
| HCQ | 0.51 (0.10-2.62) | 0.42 | 1.85 (0.71-4.81) | 0.21 | |
| LEF, MMF, AZA, MTX or HCQ | 0.31 (0.06-1.45) | 0.14 | 2.21 (0.95-5.13) | 0.07 | |
6.
31例随访患者的危险因素与疾病完全缓解之间的关系
Association between risk factor and complete response among the 31 patients with follow-up data
| Item | Complete response HRa (95% CI) | P |
| CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; IgG: Immunoglobulin G; EMG: Electromyologram; MRI: Magnetic resonance imaging. a Adjusted for age and gender. | ||
| Age at onset | 0.98 (0.92-1.05) | 0.60 |
| Time from symptom onset to diagnosis, per 1 month increase | 0.99 (0.96-1.02) | 0.53 |
| Autoimmune diseases | 1.43 (0.29-6.96) | 0.66 |
| Amyloidosis | 0 | 0.98 |
| Arthralgia/ arthritis | 0.23 (0.06-0.85) | 0.03 |
| Cumulative affected sites, per 1 site increase | 0.83 (0.61-1.14) | 0.26 |
| Peau d'orange | 0.46 (0.05-3.95) | 0.48 |
| Groove sign | 0.60 (0.18-2.03) | 0.41 |
| Eosinophilia | 1.13 (0.33-3.90) | 0.84 |
| Elevated CRP | 1.27 (0.38-4.21) | 0.70 |
| Elevated ESR | 0.25 (0.03-2.14) | 0.21 |
| Elevated IgG | 0.25 (0.05-1.18) | 0.08 |
| EMG abnormalities | 3.84 (0.35-42.50) | 0.27 |
| MRI shows muscle inflammation | 0.86 (0.17-4.24) | 0.85 |
| High-dose corticosteroid therapy | 0.35 (0.10-1.21) | 0.10 |
2.6. 超声在EF中的应用价值
37例患者进行了超声检查，共47例次，其中前臂超声36例，小腿超声11例。34/36例（94.4%）前臂超声提示浅筋膜及深筋膜增厚，11/11例小腿超声均有浅筋膜及深筋膜增厚。我们同时评估了10例健康志愿者的筋膜超声，筋膜平均厚度0.8（0.4~1.0）mm（表 7）。6例患者复查了超声，基线和复查时筋膜平均厚度分别为2.0（0.7~3.4）mm、1.3（0.5~1.9）mm，其中5/6例患者随访时筋膜厚度较基线下降。
7.
EF患者及健康对照者的超声结果
Ultrasound findings of the patients with eosinophilic fasciitis and healthy controls [Mean (range)]
| Group | TSF of forearm | TDF of forearm | TSF of lower leg | TDF of lower leg |
| EF (n=37) | 1.8 mm (0.5-4.1 mm) | 1.9 mm (0.7-3.4 mm) | 2.5 mm (1.1-4.6 mm) | 2.3 mm (1.2-5.6 mm) |
| HC (n=10) | 0.7 mm (0.4-1.0 mm) | 0.9 mm (0.6-1.0 mm) | 0.7 mm (0.4-1.0 mm) | 0.9 mm (0.8-1.0 mm) |
共26例患者同时进行了超声及MRI检查，超声提示筋膜增厚与MRI提示筋膜增厚/炎症间的Kappa值为0.91。共14例患者同时进行了前臂超声及前臂MRI检查，超声与MRI间的Kappa值为0.95。共6例患者同时进行了小腿超声及小腿MRI检查，超声与MRI间的Kappa值为1。
23/45例（51.1%）患者根据临床特征和活检结果进行诊断（其中20/23例有MRI异常），10/45例（22.2%）患者根据临床和MRI异常进行诊断，9/45例（20%）患者根据临床和超声异常进行诊断，仅3/45例（6.7%）根据临床特征及化验结果进行诊断。
3. 讨论
嗜酸性筋膜炎是一种少见病，多为小样本病例报道，目前已知的最大样本量的研究为119例多中心回顾性研究[15]，本研究回顾了近16年来在我中心就诊的45例EF患者的临床资料，旨在描述EF的临床特征、治疗及预后情况，以提高对该病的认识。我们注意到，对于曾复发的、受累部位广的、IgG升高的且没有发热的患者，可考虑大剂量激素治疗（≥200 mg/d，连续3~5d），以便更好地控制患者的筋膜炎症的症状。
目前对EF尚缺乏统一认可的诊断标准，多根据临床、活检及影像学结果进行诊断。高频超声具有快速、安全、无创、可靠等优势，在过去二十年里，已经成为诊断和随诊风湿病患者的一项成熟的影像技术[16]。本研究发现EF患者的超声提示皮下浅筋膜及深筋膜厚度增加，超声检查与MRI结果间的一致性很好，有助于EF的诊断与疗效评估。
本研究纳入的EF患者以男性多见，发病年龄16~64岁，与既往的一些研究类似[17, 18]，剧烈运动是最常见的诱因（高强度训练、劳作等，1例患者在打高尔夫球后出现症状），其他诱因包括感染、药物、外伤等，少部分患者合并有自身免疫性疾病、硬斑病、肿瘤等。本研究发现一例接种新冠疫苗后诊断EF的患者（既往体健），近期亦有相关报道[19]：该患者既往有局限性硬斑病，在接种疫苗后出现EF的症状，经治疗后症状好转。推测该硬斑病患者皮肤胶原代谢异常，疫苗成分可能在结构上与自身免疫性疾病的抗原相似，因此接种后可能形成交叉反应性抗体，从而发病[20]。我们建议对新冠大流行期间新发的EF患者，应同时追溯其疫苗接种史，评估出现其他自身免疫性疾病的可能，以便及时调整治疗策略，改善患者预后。
我们发现EF患者以对称性四肢受累为主，前臂、小腿多见，临床多表现为皮下组织肿胀、紧硬，部分有皮肤紧硬，近半数出现“沟征”、关节痛/炎以及手关节屈曲挛缩（“祈祷征”），少部分患者查体发现“橘皮征”，皮肤色素沉着较色素脱失多见，部分患者以关节痛或关节炎起病，没有滑膜增生所致的滑膜炎有助于鉴别。此外，本研究还发现2例手指肿胀，1例颜面肿胀紧硬及5例雷诺现象，既往研究[21-23]提示EF无手指、颜面紧硬及雷诺现象，以此与系统性硬化症相鉴别，但近期也有EF患者伴有手指肿胀及雷诺现象的报道[18, 24]。因此，对于这部分患者在鉴别诊断时需更加谨慎，排除诊断显得尤为重要。
本研究中多数EF患者有外周血嗜酸性粒细胞及丙种球蛋白升高，部分伴炎症指标升高（CRP、ESR）。自身抗体、低补体血症及免疫球蛋白的升高，提示EF可能存在自身免疫的异常。嗜酸细胞对激素治疗敏感，如果就诊前曾使用过激素常常掩盖嗜酸细胞高的现象，而增加诊断与鉴别的难度。我们发现2例患者有肌酸激酶的升高，部分患者的MRI发现肌肉炎症，虽然肌电图没有发现肌源性损害，但仍提示EF合并肌炎的可能，Liu等[25]的报道进一步证实了这一情况。我们发现7例皮肤组织病理及3例腹壁脂肪病理刚果红染色阳性，经筛查无其他脏器受累，亦未发现血液病证据，考虑EF可继发淀粉样病变可能，且这部分患者预后相对差。提示嗜酸性筋膜炎的病因可能多样化，预后也不同，个体化的治疗是需要。
MRI可以识别皮肤、皮下筋膜、肌肉的水肿及炎症，广泛地应用于EF的诊断及疗效评估。Narula等[10]发现，对于疑似EF的患者，超声也是一种快速、安全、廉价、可靠的诊断方法。多项研究提示EF患者的超声表现为筋膜厚度增加、高回声“双轨征”以及可压缩性下降，在治疗后这些表现均可消失[11, 26-29]。本研究中所有的MRI均发现有筋膜的增厚/炎症，超声下筋膜增厚与MRI结果间的一致性很好。
EF的治疗优先推荐使用糖皮质激素，激素对60% 的EF患者有效[23]，对于无效或复发的患者，可加用免疫抑制剂或使用生物制剂治疗[12-14]。Lebeaux等[30]发现，接受糖皮质激素冲击治疗的患者有更高的缓解率及更低的免疫抑制剂使用率。我们推荐，对于曾复发的、受累部位广的、IgG升高的且没有发热的患者，可考虑大剂量激素的治疗以改善患者预后。诊断延迟6个月以上与不良预后相关的可能性高达14.7倍[30]，本研究纳入的患者从出现症状到诊断平均时间为18.4个月，因此，早诊断、早治疗依旧是改善患者预后的良方。本研究发现，29/31例（93.5%）患者治疗后改善，其中12/31例（38.7%）的患者可停用激素，提示该病预后相对良好。与其他研究结果类似，本研究中24例患者使用了来氟米特，随访提示安全有效，因为例数太少，我们未发现与良好治疗反应相关的单一免疫抑制剂，因此需要前瞻性试验来进一步探索联合免疫抑制剂的效果。应该引起注意的是，本研究中，16例（35%）患者来我院就诊前因皮质激素的不当减量或停用而复发，并且未加用免疫抑制剂，耽误最佳治疗时机，影响预后。其中诊断不清，惧怕长期使用激素的副作用是主要原因。
本研究存在一定的局限性。首先，这是一项单中心回顾性研究，部分结果可能存在偏差。其次，本研究对治疗反应的定义包含了停用激素，相较于其他研究更为严苛，可能导致未发现与完全缓解相关的危险因素。
总之，在评估超声对EF患者应用价值的研究中，本研究是目前为止样本量最大的研究。我们发现，超声是诊断EF的一个有用的工具，与临床和MRI的一致性非常高。
Biographies
杨金水，硕士，主治医师，E-mail: 357790149@qq.com
万月华，硕士，医师，E-mail: 284986094@qq.com
Contributor Information
杨 金水 (Jinshui YANG), Email: 357790149@qq.com.
万 月华 (Yuehua WAN), Email: 284986094@qq.com.
张 江林 (Jianglin ZHANG), Email: zhjl1966@vip.sina.com.
朱 剑 (Jian ZHU), Email: jian_jzhu@126.com.
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