|
上期回顾 口腔或鼻咽溃疡 溃疡有两种形式：具备LE典型组织学变化（表现为口腔盘状皮损）的溃疡（图2D）和符合口腔溃疡特性的非特异性溃疡。狼疮特异性皮损开始为孤立性红斑和出血性斑块，后发展为盘状溃疡伴网状边界。皮损常见于硬腭（图2E），无痛感。相反，非特异性口腔溃疡通常自觉疼痛，伴口腔黏膜、唇和鼻中隔多样皮损，同时有出血倾向。口腔和鼻咽溃疡常见于JSLE和成人SLE患者疾病活动和病情缓解时。
弥漫性非瘢痕性秃发 秃发常表现为广泛脱发，头皮无炎性症状。JSLE和成人SLE患者出现弥漫性非瘢痕性秃发通常表明疾病活动。然而，其可能在严重狼疮爆发三个月后出现；如休止期脱发，是一种非特异性表现，可在任何重大系统性紊乱之后出现。JSLE患者可出现其他形式的秃发包括狼疮发（头皮表面毛发稀疏）、斑片状非疤痕性秃发（轻度红斑、分散性斑片状脱发）、斑秃。 网状青斑 皮损更常见于患有抗磷脂综合征的青少年和成人患者。其特点为皮肤可见红斑或青紫色变色的网状模式，常见于下肢。尚不知病因及其与全身性疾病活动的关系，但其可能由血管阻塞和血液粘度引起。 雷诺现象 雷诺现象特点为局限于指趾的典型的三期颜色改变; 早期苍白（白色或发白），随后青紫（蓝色），最后潮红（红色或反应性充血）。这种颜色变化顺序是寒冷或情绪压力刺激引发的血管痉挛过度的结果，回暖后通常可恢复。尚未证明，这种症状与全身性疾病有关。 大疱性SLE 大疱性皮损十分罕见，但最常见于年轻人和非裔美国妇女中。其特征为脸部、颈部、上部躯干可见多种、紧张水疱/大疱。尽管大疱性SLE与其他水疱症状相似，但确诊标准为：（a）广泛的水疱皮损；（b）组织病理学示表皮下水疱伴真皮侧急性中性粒细胞浸润；（c）直接或间接免疫荧光检查示，基底膜带真皮侧可见IgG；(d) 盐裂皮肤间接免疫荧光法可见Ⅶ型胶原抗体；（e）氨苯砜治疗有效。尚未证明大疱型SLE和系统性性疾病活动有关。 其他LE非特异性皮损 其他皮损包括：皮肤钙质沉着症、黑棘皮症、低补体血症性荨麻疹性血管炎（在JSLE患者中十分罕见），同时据报道，成年SLE患者中可见类风湿结节、皮肤松垂、红斑性肢痛病。 皮肤型狼疮的诊断 发病时仔细的临床评估足以诊断皮肤黏膜狼疮皮损。皮肤组织病理学检查可能有效，但鉴于儿童术后会留疤痕，应慎重。基于ACR标准，JSLE实验室检查也能引导和支持JSLE患者受累皮损的诊断。此外，一些研究结果通常与特定的皮损相关。例如，JSLE患者中检测出的抗Ro/SSA，常为SCLE表现。 组织病理学 组织病理学结果示，JSLE和成人SLE受累皮损通常相似。LE特异性皮损典型皮肤组织病理学表现为界面皮炎伴基底膜损伤。真皮和皮肤附属器中发现轻度至重度炎症伴血管周围淋巴细胞和中性粒细胞浸润，称为白细胞碎裂性血管炎。真皮层胶原束和汗腺之间明显可见丰富的黏蛋白细胞外沉积。尤其是，DLE皮肤组织病理学表现为典型特征：基底细胞液化变性；基底膜增厚；正角化伴真皮上部毛囊堵塞。随后，表皮萎缩伴基底膜明显增厚。最终网状真皮层胶原束和汗腺之间，可见真皮纤维化和毛囊萎缩伴丰富的黏蛋白细胞外沉积。 组织病理学特点取决于非特异性狼疮皮损类型，而不具有疾病的特异性。例如，JSLE皮肤血管炎表现为小血管白细胞碎裂性血管炎包括内皮细胞损伤、纤维蛋白沉积、炎性细胞浸润（以中性粒细胞为主）和核尘。这些现象可见于患有其他系统性疾病如过敏性紫癜、儿童皮肌炎、全身型幼年特发性关节炎的青少年患者。 免疫荧光结果 免疫荧光法不常用于诊断伴皮肤黏膜皮损的JSLE患者，但却能为诊断提供必要的证据。直接免疫荧光示，基底细胞膜带或真皮表皮交接处（皮损狼疮带试验）IgG、IgM和补体因子（C3）带状沉积。然而，可能出现假阳性结果，特别是在日光暴晒区域。非损伤皮肤活检（非损伤性狼疮带试验）示免疫沉积。 处理 需要对系统性疾病状况第一时间做仔细评估，因为疾病缓解时皮肤粘膜表现也会消退。治疗要根据疾病的严重性和器官受累情况。少数皮肤疾病，外用糖皮质激素可能会有所帮助。更广泛疾病或累及全身的疾病，短期内全身应用糖皮质激素伴羟氯喹和/或免疫抑制剂治疗。表2总结了常用于JSLE患者皮肤黏膜皮损的治疗方法及其常见副作用。 表2常用于幼年系统性红斑狼疮（JSLE）患者皮肤黏膜狼疮皮损的治疗方法 防晒霜 皮肤黏膜狼疮皮疹常具有高度光敏性，由UVA 和 UVB引起。儿童应避免长时间日晒，日常需穿防晒服（包括戴帽子）。有效的物理和化学防晒剂包括：二氧化钛、氧化锌、醋酸生育酚和黄酮类化合物。这些可用于儿童，特别是需在阳光暴晒前使用。热带地区儿童很难避免日晒，因此父母及老师应注意UV防护。缺乏阳光照射的受累个体可能出现维生素D偏低；若这样，应考虑补充维生素D3和钙。 糖皮质激素 因糖皮质激素治疗皮肤黏膜狼疮皮损十分有效，常外用糖皮质激素治疗JSLE患者。强效的糖皮质激素有助于缓解皮损。随后可逐渐减少剂量，直至停用。通常面部和身上的皮损，使用轻度至中度的糖皮质激素。然而，敏感部位（例如眼睛周围、腹股沟和生殖器）首选长期使用钙调神经磷酸酶抑制剂，以防皮肤变薄。如果皮损为JSLE的一部分，那么只有使用系统疗法控制疾病，其才能改善。在这一组中，治疗更侧重于控制系统性疾病。 皮内注射糖皮质激素可用于治疗青少年DLE，特别是皮损位于头皮时，能最小化瘢痕性秃发，而全身应用糖皮质激素在短期内能有效缓解严重的皮肤黏膜皮损（例如多种口腔溃疡，或严重皮肤血管炎伴溃疡和坏死）。然而，因其严重副作用，应避免长期使用。因此，应慎重考虑患病区域、给药途径、糖皮质激素的药效、治疗长度和任何副作用，特别是治疗JSLE患者时。 抗疟药-氨基喹啉 羟氯喹能有效治疗皮肤黏膜狼疮皮损，因此当需要全身治疗时，首选羟氯喹。尚不确定这些药物的作用机理，但包括可预防抗原的刺激的Toll样受体阻滞作用（据认为这一过程参与该疾病的发病机制）。需慎重考虑其对JSLE患者的严重副作用，特别是不可逆的眼损伤，因其依赖于每日最大剂量，而不是累积剂量。因此，使用理想体重计算儿童每日服用剂量非常重要。建议进行常规眼部检查。 其他药物 局部外用钙调神经磷酸酶抑制剂，如他克莫司和吡美莫司，有助于改善皮损（对局部外用糖皮质激素特别敏感，容易引起皮肤萎缩，如眼睑，面部和擦烂区和耐受性良好的皮损）。通常在JSLE患者中，类固醇免疫抑制剂（如甲氨蝶呤、硫唑嘌呤和吗替麦考酚酯）同羟氯喹共同起作用。 JSLE患者常表现为皮肤黏膜表现，因而识别皮损有助于正确诊断。在任何儿童出现皮肤黏膜狼疮特征时，评估全身性疾病状况至关重要，因为其可能需要数年符合诊断标准。因此，任何出现SLE相关皮肤黏膜皮损的儿童需要定期进行评估和监控。防晒至关重要，应当予以鼓励，以防止SLE症状恶化和加重。在成人患者中，狼疮相关皮肤疾病通常是局部的。在儿童中，皮损通常与全身性疾病相关，为了能充分控制疾病，需要全身应用免疫抑制剂治疗。 Oral or nasopharyngeal ulcers There are two types of these ulcers: those with classical LE histological changes representing oral discoid lesions (Figure 2D) and non-specific ulcers in keeping with aphthous ulceration. The lupus specific lesions begin with solitary erythema and hemorrhaging patches before developing into discoid ulcers with a reticulate border. Typically, the lesions are painless and located on the hard palate (Figure 2E). In contrast, the nonspecific aphthous ulcers are usually painful, with multiple lesions on the buccal mucosa, lips and nasal septum, whilst also having a tendency to bleed. Oral and nasopharyngeal ulcers are normally found during active disease and subside with disease remission in JSLE and adult SLE patients. Figure 2 LE nonspecific skin lesions: (A) Vasculitic purpura at left palm; (B) Cutaneous vasculitis at right cheek, eyelid and nose; (C) Cutaneous urticarial vasculitis at right palm; (D) Oral discoid lesion on the lateral border of the tongue; and (E) Oral ulceration and a discoid lesion on the hard palate. Diffuse non-scarring alopecia Alopecia often presents with generalized hair loss without signs of inflammation on the scalp. Diffuse, non-scarring alopecia in JSLE and adult SLE patients usually suggests active disease. However, it may occur three months after a severe lupus flare; e.g. Telogen effluvium, which is a nonspecific finding and can also occur after any significant systemic disturbance. Other forms of alopecia also found in JSLE patients include lupus hair (thin and weakened hair at the periphery of the scalp), patchy non-scarring alopecia (mild erythematous, scattered patchy hair loss) and alopecia areata. Livedo reticularis These lesions present more commonly in both juvenile and adult patients who are diagnosed with anti-phospholipid syndrome. It is characterized by erythematous or cyanotic discoloration of the skin with reticulated (net-like) pattern, usually on the lower extremities. The etiology and correlation with systemic disease activity are unknown, but vascular obstruction and blood viscosity may be the cause. Raynaud’s phenomenon Raynaud’s phenomenon is characterized by the classic “triphasic” color changes limited to the digits; pallor (white or blanching) followed by the cyanosis (blue) then erythema (red or reactive hyperemia). This color change sequence results from excessive vasospasms triggered by cold exposure or emotional stress, and can often be reversed following re-warming. There is no evidence to suggest that this symptom correlates with systemic disease. Bullous SLE The bullous lesions are rare and most commonly reported in young adults and African-American women. It is characterized by multiple, tense vesicles/bullae usually on face, neck and upper trunk. As bullous SLE is similar to other vesicobullous conditions, the criteria needed to make a diagnosis are: (a) acquired widespread cutaneous vesicobullous lesions; (b) subepidermal blister with acute neutrophilic infiltration in dermis confirmed by histopathology; (c) evidence of IgG at the dermal side of the basement membrane zone by direct or indirect immunofluorescence; (d) presence of antibodies to collagen type Ⅶ by indirect immunofluorescence on salt-split skin and (e) a tendency to respond to Dapsone . There is no evidence of any correlation between bullous SLE and systemic disease activeity . Other LE nonspecific lesions Other lesions include: calcinosis cutis, acanthosis nigricans, hypocomplementaemic urticarial vasculitis (very rare in JSLE patients), whilst rheumatoid nodules, anetoderma and erythromelalgia have been reported in adult SLE. Diagnosis of cutaneous lupus Careful clinical assessment at presentation is usually sufficient to make a diagnosis of mucocutaneous lupus lesions. Skin histopathology may be useful, but this needs to be carefully considered in children because of scarring after this procedure. Laboratory investigations in JSLE based on the ACR criteria can also guide and support the diagnosis of the affected lesions in patients diagnosed with JSLE. Moreover, some of these findings are more commonly associated with particular lesions; for example, anti-Ro/SSA is often detected in JSLE patients presenting with SCLE . Histopathology Histopathological findings of the affected lesions of JSLE and adult SLE usually show similarities. Characteristically, skin histopathology of a LE specific lesion is interface dermatitis with basement membrane damage. Mild to severe inflammation is present in the dermis and skin appendages with perivascular lymphocytic and neutrophil infiltrates called leukocytoclastic vasculitis. Abundant extracellular deposition of mucin is markedly observed in the dermis between the collagen bundles and sweat glands. In particular, skin histopathology of DLE shows classical features: vacuolar degeneration of basal cell layer; thickened basement membrane; orthokeratosis with follicular plugging in upper dermis. Epidermal atrophy with marked thickening of basement membrane occurs in the later stages. Dermal fibrosis and follicular atrophy with abundant extracellular mucin deposits between collagen bundles in reticular dermis and sweat glands are eventually seen. The histopathology features attributed to nonspecific lupus vary depending on the type of lesions and are not pathognomonic of the condition. For example, cutaneous vasculitis in JSLE shows small vessel leukocytoclastic vasculitis including endothelial cell damage, fibrin deposition, inflammatory cell infiltrate (predominantly neutrophils) and nuclear dust. These findings can be found in juvenile patients with other systemic diseases such as henoch-sch?nlein purpura, juvenile dermatomyositis and systemic juvenile idiopathic arthritis. Immunofluorescence findings Immunofluorescence is not routinely used for the diagnosis in JSLE patients with mucocutaneous lesions, but it can be helpful when supporting evidence for making a diagnosis is needed. Direct immunofluorescence shows band-like deposits of IgG, IgM and complement factor (C3) in the basement membrane zone or dermo-epidermal junction (lesional lupus band test). However, false positive findings can occur especially in sun-exposed areas. Immune deposits are also found in non-lesional skin biopsies (non-lesional lupus band test). Management Careful assessment of systemic disease status is first needed, as inducing disease remission will lead to resolution of the mucocutaneous lesions. Treatment is tailored to disease severity and organ involvement. In limited cutaneous disease, topical corticosteroids may be helpful. In more extensive disease or where there is systemic involvement, short courses of systemic corticosteroids with concurrent use of hydroxychloroquine and/or immunosuppressive therapies are indicated. Table 2 summarizes the commonly used treatments of mucocutaneous lesions and their common side effects in JSLE patients. Table 2 Summary of commonly used treatment in mucocutaneous lupus lesions in juvenile systemic lupus erythematosus (JSLE) Sunscreen Mucocutaneous lupus lesions are generally highly photosensitive, triggered by both UVA and UVB. Children are advised to avoid prolonged sun exposure and routinely wear protective clothing (including hats). Very potent physical and chemical sunscreens include: titanium dioxide, zinc oxide, tocopheryl acetate and flavonoids. These can be used in children, particularly before direct sun exposure. Children in tropical countries may have some difficulties of sun avoidance; thus, parents as well as school teachers are encouraged to be vigilant about UV protection. Lack of sun exposure in affected individuals can sometimes result in low vitamin D levels; if so, vitamin D3 and calcium supplements should be considered. Corticosteroids Topical corticosteroids are commonly used in JSLE patients as they are very effective for mucocutaneous lupus lesions. High potency corticosteroids are necessary to induce remission of the lesions. This can then be followed by gradual tapering of the dose to discontinuation. Mild to moderate potency corticosteroids are usually applied to lesions on the face and body. However, calcineurin inhibitors are preferred in delicate areas (e.g. around the eyes, groin and genitalia) for more prolonged use to prevent skin thinning. If the lesions are part of JSLE, then they will only be improved along with the systemic therapies used to control the disease. In this group, treatments should be more focused on controlling the systemic disease. An intralesional corticosteroid injection can be used in adolescents with DLE, particularly on the scalp, to minimize the scarring alopecia, whilst systemic corticosteroids are very helpful in the short term of induce remission of severe mucocutaneous lesions (e.g. multiple oral ulcers, or severe cutaneous vasculitis with ulceration and necrosis). However, these should be avoided for prolonged periods due to serious side effects. Therefore, the affected areas, the route of administration, the potency of corticosteroids, length of treatment and any side effects should be carefully considered, particularly in JSLE patients. Aminoquinolone antimalarial drugs Hydroxychloroquine demonstrates good efficacy with mucocutaneous lupus lesions and is therefore the first line treatment when systemic therapy is required. The mechanism of action of these drugs is uncertain but includes Toll-Like Receptor blockade that prevent antigen stimulation, a process thought to be involved in the pathogenesis of the disease. Serious side effects in JSLE, particularly irreversible ocular damage, require careful consideration as they depend on the maximum daily dose rather than the cumulative dose. Therefore, using the ideal body weight for calculation of the daily dose in children is important. Routine eye check-ups is recommended. Other medications Topical calcineurin inhibitors, such as tacrolimus and primecrolimus, are useful for lesions that are particularly sensitive to topical corticosteroids and prone to skin atrophy, such as on the eyelids, face and intertriginous areas and are well-tolerated. Steroid sparing immunosuppressive agents in JSLE patients (e.g. methotrexate, azathioprine and mycophenolate mofetil), are usually initiated along with hydroxychloroquine. Patients with JSLE commonly present with mucocutaneous manifestations, and it is therefore important to recognize the lesions to make an accurate diagnosis. Assessment of systemic disease status in any child presenting with mucocutaneous lupus features is crucial as it may take a number of years to meet the diagnostic criteria. Therefore, any child with mucocutaneous lesions associated with SLE needs to be regularly reassessed and monitored. Sun protection is vital and should be encouraged to prevent both worsening of the symptoms and exacerbation of SLE. In adult patients, lupus associated skin disease is often localized. In children, lesions are usually associated with systemic disease and require treatment with systemic immunosuppressive drugs in order to achieve adequate disease control. 由MediCool医库软件吴茵芸 编译，上海市皮肤病医院陈裕充博士审核 原文来自：Chiewchengchol et al. Pediatric Rheumatology 2015, 13:1 上期回顾 点击下面标题可直接阅读前五期内容 |
|
|
