Albuquerque Julia V de, Andriolo Brenda Ng, Vasconcellos Monica Ra, Civile Vinicius T, Lyddiatt Anne, Trevisani Virginia Fm
Cochrane Brazil, Centro de Estudos de Saúde Baseada em Evidências e Avaliação Tecnológica em Saúde, Rua Borges Lagoa, 564 cj 63, São Paulo, São Paulo, Brazil, 04038-000.
Cochrane Database Syst Rev. 2019 Jul 16;7(7):CD005027. doi: 10.1002/14651858.CD005027.pub5.
Morphea (morphoea) is an immune-mediated disease in which excess synthesis and deposition of collagen in the skin and underlying connective tissues results in hardened cutaneous areas. Morphea has different clinical features according to the subtype and stage of evolution of the disease. There is currently no consensus on optimal interventions for morphea.
To assess the effects of treatments for people with any form of morphea.
We searched the following databases up to July 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, and five trial registers. We checked the reference lists of included studies for further references to relevant randomised controlled trials.
Randomised controlled trials of topical, intralesional, or systemic treatments (isolated or combined) in anyone who has been clinically diagnosed by a medical practitioner with any form of morphea. Eligible controls were placebo, no intervention, any other treatment, or different doses or duration of a treatment.
We used standard methodological procedures expected by Cochrane. The primary outcomes were global improvement of disease activity or damage assessed by a medical practitioner or by participants, and adverse effects. Secondary outcomes were improvement of disease activity and improvement of disease damage. We used GRADE to assess the quality of the evidence for each outcome.
We included 14 trials, with a total of 429 randomised participants, aged between 3 and 76 years. There were juvenile and adult participants; over half were female, and the majority had circumscribed morphea, followed by linear scleroderma. The settings of the studies (where described) included a dermatologic centre, a national laboratory centre, paediatric rheumatology and dermatology centres, and a university hospital or medical centre.The studies evaluated heterogenous therapies for different types of morphea, covering a wide range of comparisons. We were unable to conduct any meta-analyses. Seven studies investigated topical medications, two evaluated intralesional medications, and five investigated systemic medications. The study duration ranged from seven weeks to 15 months from baseline.We present here results for our primary outcomes for our four key comparisons. All of these results are based on low-quality evidence.The included studies were at high risk of performance, detection, attrition, and reporting bias.Global improvement of disease activity or damage after treatment may be higher with oral methotrexate (15 mg/m², maximum 20 mg, once a week, for 12 months or until disease flare) plus oral prednisone (1 mg/kg a day, maximum of 50 mg, in a single morning dose, for three months, and one month with gradually decreased dose until discontinuation) than with placebo plus oral prednisone in children and adolescents with active morphea (linear scleroderma, generalised morphea or mixed morphea: linear and circumscribed) (risk ratio (RR) 2.31, 95% confidence interval (CI) 1.20 to 4.45; number needed to treat for an additional beneficial outcome (NNTB) 3; 1 randomised controlled trial (RCT); 70 participants, all juvenile). This outcome was measured 12 months from the start of treatment or until flare of the disease. Data were not available separately for each morphea type. There may be little or no difference in the number of participants experiencing at least one adverse event with oral methotrexate (26/46) or placebo (11/24) (RR 1.23, 95% CI 0.75 to 2.04; 1 RCT; 70 participants assessed during the 12-month follow-up). Adverse events related to methotrexate included alopecia, nausea, headache, fatigue and hepatotoxicity, whilst adverse events related to prednisone (given in both groups) included weight gain (more than 5% of body weight) and striae rubrae.One three-armed RCT compared the following treatments: medium-dose (50 J/cm²) UVA-1; low-dose (20 J/cm²) UVA-1; and narrowband UVB phototherapy. There may be little or no difference between treatments in global improvement of disease activity or damage, as assessed through the modified skin score (where high values represent a worse outcome): medium-dose UVA-1 phototherapy versus low-dose UVA-1 group: MD 1.60, 95% CI -1.70 to 4.90 (44 participants); narrowband UVB phototherapy versus medium-dose UVA-1 group: MD -1.70, 95% CI -5.27 to 1.87 (35 participants); and narrowband UVB versus low-dose UVA-1 group: MD -0.10, 95% CI -2.49 to 2.29 (45 participants). This RCT included children and adults with active morphea (circumscribed morphea, linear scleroderma (with trunk/limb variant and head variant), generalised morphea, or mixed morphea), who received phototherapy five times a week, for eight weeks. Outcomes were measured at eight weeks from the start of treatment.Safety data, measured throughout treatment, from the same RCT (62 participants) showed that treatment with UVA-1 phototherapy may cause mild tanning compared to narrowband UVB: narrowband UVB versus medium-dose UVA-1: RR 0.03, 95% CI 0.00 to 0.42; 35 participants; narrowband UVB versus low-dose UVA-1: RR 0.03, 95% CI 0.00 to 0.41; 45 participants. However, there may be no difference in the number of participants reporting mild tanning when comparing medium and low dose UVA-1 phototherapy (RR 1.00, 95% CI 0.91 to 1.10; 44 participants). Transient erythema was reported in three participants with narrowband UVB and no participants in the low- or medium-dose UVA-1 groups.
AUTHORS' CONCLUSIONS: Compared to placebo plus oral prednisone, oral methotrexate plus oral prednisone may improve disease activity or damage in juvenile active morphea (linear scleroderma, generalised morphea or mixed morphea: linear and circumscribed), but there may be a slightly increased chance of experiencing at least one adverse event.When medium-dose UVA-1 (50 J/cm²), low-dose UVA-1 (20 J/cm²), and narrowband UVB were compared against each other in treating children and adults with active morphea (circumscribed morphea, linear scleroderma, generalised morphea and mixed morphea), there may be little or no difference between these treatments on global improvement of disease activity or damage. UVA-1 phototherapy may cause more mild tanning than narrowband UVB, but there may be no difference between medium- and low-dose UVA-1 phototherapy. These results are based on low-quality evidence.Limitations of data and analyses include risk of bias and imprecision (small number of participants or events and wide confidence intervals). We encourage multicentre RCTs to increase sample size and evaluate, with validated tools, different treatment responses according to the subtypes of morphea and age groups.
硬斑病是一种免疫介导性疾病，皮肤及皮下结缔组织中胶原蛋白过度合成与沉积导致皮肤硬化区域形成。硬斑病根据疾病亚型及演变阶段具有不同临床特征。目前对于硬斑病的最佳干预措施尚无共识。
评估各种治疗方式对硬斑病患者的疗效。
截至2018年7月，我们检索了以下数据库：Cochrane皮肤专科注册库、CENTRAL、MEDLINE、Embase、LILACS以及五个试验注册库。我们检查了纳入研究的参考文献列表，以进一步查找相关随机对照试验的参考文献。
针对经医生临床诊断为任何形式硬斑病的患者进行的外用、皮损内或全身治疗（单独或联合）的随机对照试验。合格的对照为安慰剂、无干预、任何其他治疗，或治疗的不同剂量或疗程。
我们采用了Cochrane期望的标准方法程序。主要结局为医生或参与者评估的疾病活动或损害的整体改善情况以及不良反应。次要结局为疾病活动改善情况和疾病损害改善情况。我们使用GRADE评估每个结局的证据质量。
我们纳入了14项试验，共429名随机参与者，年龄在3至76岁之间。有青少年和成年参与者；超过一半为女性，大多数患有局限性硬斑病，其次是线状硬皮病。研究的开展地点（如有描述）包括皮肤科中心、国家实验室中心、儿科风湿病和皮肤科中心以及大学医院或医疗中心。这些研究评估了针对不同类型硬斑病的多种不同疗法，涵盖广泛的比较。我们无法进行任何荟萃分析。七项研究调查了外用药物，两项评估了皮损内药物，五项调查了全身药物。研究持续时间从基线起为7周-15个月。我们在此呈现四项关键比较的主要结局结果。所有这些结果均基于低质量证据。纳入的研究在实施、检测、失访和报告偏倚方面风险较高。对于患有活动性硬斑病（线状硬皮病、泛发性硬斑病或混合性硬斑病：线状和局限性）的儿童和青少年，口服甲氨蝶呤（15mg/m²，最大20mg，每周一次，共12个月或直至疾病复发）加口服泼尼松（1mg/kg/天，最大50mg，晨起单次给药，共3个月，随后1个月逐渐减量直至停药）治疗后疾病活动或损害的整体改善情况可能高于安慰剂加口服泼尼松（风险比（RR）2.31，95%置信区间（CI）1.20至4.45；额外获得有益结局所需治疗人数（NNTB）3；1项随机对照试验（RCT）；70名参与者，均为青少年）。该结局在治疗开始后12个月或直至疾病复发时进行测量。每种硬斑病类型的数据未单独提供。口服甲氨蝶呤（26/46）或安慰剂（11/24）的参与者中至少发生一次不良事件的人数可能几乎没有差异（RR 1.23，95%CI 0.75至2.04；1项RCT；70名参与者在12个月随访期间进行评估）。与甲氨蝶呤相关的不良事件包括脱发、恶心、头痛、疲劳和肝毒性，而与泼尼松相关的不良事件（两组均使用）包括体重增加（超过体重的5%）和萎缩纹。一项三臂RCT比较了以下治疗方法：中剂量（50J/cm²）UVA-1；低剂量（20J/cm²）UVA-1；以及窄谱UVB光疗。通过改良皮肤评分评估（高分表示更差结局），各治疗方法在疾病活动或损害的整体改善方面可能几乎没有差异：中剂量UVA-1光疗与低剂量UVA-1组比较：MD 1.60，95%CI -1.70至4.90（44名参与者）；窄谱UVB光疗与中剂量UVA-1组比较：MD -1.70，95%CI -5.27至1.87（35名参与者）；窄谱UVB与低剂量UVA-1组比较：MD -0.10，95%CI -2.49至2.29（45名参与者）。该RCT纳入了患有活动性硬斑病（局限性硬斑病、线状硬皮病（有躯干/肢体型和头部型）、泛发性硬斑病或混合性硬斑病）的儿童和成人，他们每周接受5次光疗，共8周。结局在治疗开始后8周进行测量。来自同一RCT（62名参与者）的整个治疗过程中的安全性数据显示，与窄谱UVB相比，UVA-1光疗可能会导致轻度晒黑：窄谱UVB与中剂量UVA-1比较：RR 0.03，95%CI 0.00至0.42；35名参与者；窄谱UVB与低剂量UVA-1比较：RR 0.03，95%CI 0.00至0.41；45名参与者。然而，比较中剂量和低剂量UVA-1光疗时，报告轻度晒黑的参与者人数可能没有差异（RR 1.00，95%CI 0.91至1.10；44名参与者）。窄谱UVB组有3名参与者报告出现短暂红斑，低剂量或中剂量UVA-光疗组无参与者报告。
与安慰剂加口服泼尼松相比，口服甲氨蝶呤加口服泼尼松可能改善青少年活动性硬斑病（线状硬皮病、泛发性硬斑病或混合性硬斑病：线状和局限性）的疾病活动或损害，但至少发生一次不良事件的几率可能略有增加。在治疗患有活动性硬斑病（局限性硬斑病、线状硬皮病、泛发性硬斑病和混合性硬斑病）的儿童和成人时，将中剂量UVA-1（50J/cm²）、低剂量UVA-1（20J/cm²）和窄谱UVB相互比较，这些治疗方法在疾病活动或损害的整体改善方面可能几乎没有差异。UVA-1光疗可能比窄谱UVB导致更多的轻度晒黑，但中剂量和低剂量UVA-1光疗之间可能没有差异。这些结果基于低质量证据。数据和分析的局限性包括偏倚风险和不精确性（参与者或事件数量少且置信区间宽）。我们鼓励开展多中心RCT以增加样本量，并使用经过验证的工具评估根据硬斑病亚型和年龄组的不同治疗反应。
