背景:湿疹(特应性皮炎)是全球范围内最繁重的皮肤病,目前无法预防或治愈。局部抗炎治疗用于控制湿疹症状,但不同局部抗炎治疗的相对有效性和安全性存在不确定性.
目的:使用网络荟萃分析对湿疹患者局部抗炎治疗的疗效和安全性进行比较和排名。
方法:我们搜索了CochraneSkin专业注册,中部,MEDLINE,Embase和试验登记处于2023年6月29日进行,并检查了纳入研究的参考清单。
方法:我们纳入了参与者内部或参与者之间的随机对照试验(RCT),研究对象为任何年龄的湿疹患者,但排除了临床感染湿疹的试验,脂溢湿疹,接触性湿疹,或手部湿疹。我们包括至少一周的局部抗炎治疗,与另一种抗炎治疗相比,没有治疗,或媒介物/安慰剂。车辆是活性药物的载体系统,它也可以单独用作干性皮肤的润肤剂。我们排除了单独使用局部抗生素的试验,补充疗法,单独使用的润肤剂,光疗,湿包裹,和系统治疗。
方法:我们使用标准Cochrane方法。主要结果是患者报告的湿疹症状,临床医生报告的湿疹迹象和研究者的全球评估。次要结果是健康相关的生活质量,长期控制湿疹,退出治疗/研究,和局部不良反应(应用现场反应,通过患者和公众的参与,色素沉着变化和皮肤变薄/萎缩被认为是重要的问题)。我们使用CINeMA来量化我们对每个结果的证据的信心。
结果:我们纳入了291项研究,涉及45,846名具有完整湿疹严重程度的参与者,主要在高收入国家的二级保健机构进行。大多数研究包括成年人,只有31项研究仅限于12岁以下的儿童。研究通常包括男性和女性参与者,多个种族,但主要是白人。大多数研究是由行业资助的(68%)或没有报告其资金来源/详细信息。治疗持续时间和试验参与的中位数为21天和28天(范围从7天到5年),分别。使用的干预措施是局部皮质类固醇(TCS)(172),局部钙调磷酸酶抑制剂(TCI)(134),磷酸二酯酶-4(PDE-4)抑制剂(55),janus激酶(JAK)抑制剂(30),芳烃受体活化剂(10),或其他局部药剂(21)。比较物包括载体(170)或其他抗炎治疗。在272项(89.0%)有助于数据分析的试验中,有242项偏倚的风险很高,最常见的原因是对选择性报告的担忧。网络荟萃分析(NMA)仅适用于短期结果。40项试验(6482名参与者)的患者报告症状NMA报告患者报告症状为二元结局,他克莫司为0.1%(OR6.27,95%CI1.19至32.98),有效的TCS(OR5.99,95%CI2.83至12.69),和鲁索替尼1.5%(OR5.64,95%CI1.26至25.25)是最有效的,所有的信心都很低。温和的TCS,罗氟司特0.15%,和crisaborole2%是最不有效的。类别水平敏感性分析发现,有效/非常有效的TCS与有效的TCI具有相似的效力,并且比温和的TCI和PDE-4抑制剂更有效。NMA报告患者报告的症状为连续结局的29项试验(3839名参与者)中,TCS非常有效(SMD-1.99,95%CI-3.25至-0.73;低置信度)和他克莫司0.03%(SMD-1.57,95%CI-2.42至-0.72;中度置信度)最高。0.03%他克莫司的直接信息是基于一项对60名高风险偏倚参与者的试验。罗氟司特0.15%,德戈西替尼0.25%或0.5%,和tapinarof1%是最不有效的。类别水平敏感性分析发现,有效/非常有效的TCS与有效的TCI和JAK抑制剂具有相似的有效性,而轻度/中度TCS不如轻度TCI有效。另外50项试验(9636名参与者)报告了患者报告的症状作为连续结局,但不能包括在NMA中。32项试验(4121名参与者)的NMA报告临床体征为二元结果,并对有效TCS进行排名(OR8.15,95%CI4.99,13.57),他克莫司0.1%(OR8.06,95%CI3.30,19.67),鲁索替尼1.5%(OR7.72,95%CI4.92,12.10),和0.5%(OR7.61,95%CI3.72,15.58)为最有效,都有适度的信心。温和的TCS,罗氟司特0.15%,crisaborole2%,和tapinarof1%是最不有效的。类别水平敏感性分析发现,强效/非常强效的TCS比强效的TCI,轻度TCI,JAK抑制剂更有效,PDE-4抑制剂和轻度TCS和PDE-4抑制剂具有相似的效力。NMA的49项试验(5261名参与者)报告临床医生体征为连续结局,并将他克莫司0.03%(SMD-2.69,95%CI-3.36,-2.02)和非常有效的TCS(SMD-1.87,95%CI-2.69,-1.05)列为最有效,两者都有适度的信心;罗氟司特0.15%,0.3%的difamilast和1%的tapinarof被列为最不有效的。0.03%他克莫司的直接信息是基于60名具有高偏倚风险的参与者的一项试验。对于一些敏感性分析,有效的TCS,0.1%他克莫司,ruxolitinib1.5%,0.5%的德戈西替尼和0.25%的德戈西替尼成为一些最有效的治疗方法.类水平分析发现,有效/非常有效的TCS与有效的TCI和JAK抑制剂具有相似的效力,中度/轻度TCS比轻度TCI更有效。另有100项试验(22,814名参与者)报告临床医生体征为连续结局,但不能纳入NMA。研究者全球评估NMA的140项试验(23,383名参与者)报告了IGA作为二元结果,并将鲁索替尼排名为1.5%(OR9.34,95%CI4.8,18.18),德戈西替尼0.5%(OR10.08,95%CI2.65,38.37),德戈西替尼0.25%(OR6.87,95%CI1.79,26.33),非常有效的TCS(OR8.34,95%CI4.73,14.67),有效的TCS(OR5.00,95%CI3.80,6.58),和他克莫司0.1%(OR5.06,95%CI3.59,7.13)为最有效,都有适度的信心。温和的TCS,crisaborole2%,吡美莫司1%,罗氟司特0.15%,difamilast0.3%和1%,和他克莫司0.03%是最不有效的。在对低偏倚风险信息的敏感性分析中(12项试验,1639名参与者),有效的TCS,0.5%的德戈西替尼和0.25%的德戈西替尼最有效,1%的吡美莫司,罗氟司特0.15%,1%的双通司和0.3%的双通司最不有效。类别水平敏感性分析发现,有效/非常有效的TCS与有效的TCI和JAK抑制剂具有相似的效力,并且比PDE-4抑制剂更有效;轻度/中度TCS不如TCI有效,与TCI相似。6至12个月的长期结果显示,吡美莫司与溶媒相比,可能会增加1%的有效性(4项试验,2218名参与者)在成对荟萃分析中,轻度/中度TCS的治疗成功率高于吡美莫司1%(基于2045名参与者的1项试验)。83项试验的局部不良反应NMA(18,992名参与者,2424个事件)报告的应用现场反应将他克莫司排名为0.1%(OR2.2,95%CI1.53,3.17;中等置信度),crisaborole2%(OR2.12,95%CI1.18,3.81;高置信度),他克莫司0.03%(OR1.51,95CI1.10,2.09;置信度低),和吡美莫司1%(OR1.44,95%CI1.01,2.04;置信度低)最有可能引起部位反应。非常有效,强力,中度,和轻度TCS最不可能引起部位反应。8项试验的NMA(1786名参与者,3个事件)报告色素沉着变化未发现TCS和crisaborole2%的色素沉着变化增加的证据,对温和的信心低,中等或有效的TCS和中等置信度为2%。NMA的25项试验(3691名参与者,36个事件)报告皮肤变薄没有发现短期皮肤变薄增加的证据(中位数3周,范围1-16周)使用轻度TCS(OR0.72,95%CI0.12,4.31),中度TCS(OR0.91,95%CI0.16,5.33),有效的TCS(OR0.96,95%CI0.21,4.43)或非常有效的TCS(OR0.88,95%CI0.31,2.49),所有的信心都很低。6至60个月的长期结局显示,皮肤变薄增加,轻度至强效TCS与TCI(3项试验,4069名参与者,6事件与TCS)。
结论:强效TCS,JAK抑制剂和0.1%他克莫司一直被列为最有效的局部抗炎治疗湿疹和PDE-4抑制剂中最无效的。在五个功效网络中的三个中,轻度TCS和1%的tapinarof被列为最不有效的治疗方法之一。TCI和crisaborole2%被认为最有可能引起局部应用部位反应,而TCS最不可能。我们没有发现短期TCS增加皮肤变薄的证据,但长期TCS增加。
BACKGROUND: Eczema (atopic dermatitis) is the most burdensome skin condition worldwide and cannot currently be prevented or cured. Topical anti-inflammatory treatments are used to control eczema symptoms, but there is uncertainty about the relative effectiveness and safety of different topical anti-inflammatory treatments.
OBJECTIVE: To compare and rank the efficacy and safety of topical anti-inflammatory treatments for people with eczema using a network meta-analysis.
METHODS: We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries on 29 June 2023, and checked the reference lists of included studies.
METHODS: We included within-participant or between-participant randomised controlled trials (RCTs) in people of any age with eczema of any severity, but excluded trials in clinically infected eczema, seborrhoeic eczema, contact eczema, or hand eczema. We included topical anti-inflammatory treatments used for at least one week, compared with another anti-inflammatory treatment, no treatment, or vehicle/placebo. Vehicle is a \'carrier system\' for an active pharmaceutical substance, which may also be used on its own as an emollient for dry skin. We excluded trials of topical antibiotics used alone, complementary therapies,
emollients used alone, phototherapy, wet wraps, and systemic treatments.
METHODS: We used standard Cochrane methods. Primary outcomes were patient-reported eczema symptoms, clinician-reported eczema signs and investigator global assessment. Secondary outcomes were health-related quality of life, long-term control of eczema, withdrawal from treatment/study, and local adverse effects (application-site reactions, pigmentation changes and skin thinning/atrophy were identified as important concerns through patient and public involvement). We used CINeMA to quantify our confidence in the evidence for each outcome.
RESULTS: We included 291 studies involving 45,846 participants with the full spectrum of eczema severity, mainly conducted in high-income countries in secondary care settings. Most studies included adults, with only 31 studies limited to children aged < 12 years. Studies usually included male and female participants, multiple ethnic groups but predominantly white populations. Most studies were industry-funded (68%) or did not report their funding sources/details. Treatment duration and trial participation were a median of 21 and 28 days (ranging from 7 days to 5 years), respectively. Interventions used were topical corticosteroids (TCS) (172), topical calcineurin inhibitors (TCI) (134), phosphodiesterase-4 (PDE-4) inhibitors (55), janus kinase (JAK) inhibitors (30), aryl hydrocarbon receptor activators (10), or other topical agents (21). Comparators included vehicle (170) or other anti-inflammatory treatments. The risk of bias was high in 242 of the 272 (89.0%) trials contributing to data analyses, most commonly due to concerns about selective reporting. Network meta-analysis (NMA) was only possible for short-term outcomes. Patient-reported symptoms NMA of 40 trials (6482 participants) reporting patient-reported symptoms as a binary outcome ranked tacrolimus 0.1% (OR 6.27, 95% CI 1.19 to 32.98), potent TCS (OR 5.99, 95% CI 2.83 to 12.69), and ruxolitinib 1.5% (OR 5.64, 95% CI 1.26 to 25.25) as the most effective, all with low confidence. Mild TCS, roflumilast 0.15%, and crisaborole 2% were the least effective. Class-level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and was more effective than mild TCI and PDE-4 inhibitors. NMA of 29 trials (3839 participants) reporting patient-reported symptoms as a continuous outcome ranked very potent TCS (SMD -1.99, 95% CI -3.25 to -0.73; low confidence) and tacrolimus 0.03% (SMD -1.57, 95% CI -2.42 to -0.72; moderate confidence) the highest. Direct information for tacrolimus 0.03% was based on one trial of 60 participants at high risk of bias. Roflumilast 0.15%, delgocitinib 0.25% or 0.5%, and tapinarof 1% were the least effective. Class-level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors and mild/moderate TCS was less effective than mild TCI. A further 50 trials (9636 participants) reported patient-reported symptoms as a continuous outcome but could not be included in NMA. Clinician-reported signs NMA of 32 trials (4121 participants) reported clinician signs as a binary outcome and ranked potent TCS (OR 8.15, 95% CI 4.99, 13.57), tacrolimus 0.1% (OR 8.06, 95% CI 3.30, 19.67), ruxolitinib 1.5% (OR 7.72, 95% CI 4.92, 12.10), and delgocitinib 0.5% (OR 7.61, 95% CI 3.72, 15.58) as most effective, all with moderate confidence. Mild TCS, roflumilast 0.15%, crisaborole 2%, and tapinarof 1% were the least effective. Class-level sensitivity analysis found potent/very potent TCS more effective than potent TCI, mild TCI, JAK inhibitors, PDE-4 inhibitors; and mild TCS and PDE-4 inhibitors had similar effectiveness. NMA of 49 trials (5261 participants) reported clinician signs as a continuous outcome and ranked tacrolimus 0.03% (SMD -2.69, 95% CI -3.36, -2.02) and very potent TCS (SMD -1.87, 95% CI -2.69, -1.05) as most effective, both with moderate confidence; roflumilast 0.15%, difamilast 0.3% and tapinarof 1% were ranked as least effective. Direct information for tacrolimus 0.03% was based on one trial in 60 participants with a high risk of bias. For some sensitivity analyses, potent TCS, tacrolimus 0.1%, ruxolitinib 1.5%, delgocitinib 0.5% and delgocitinib 0.25% became some of the most effective treatments. Class-level analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors, and moderate/mild TCS was more effective than mild TCI. A further 100 trials (22,814 participants) reported clinician signs as a continuous outcome but could not be included in NMA. Investigator Global Assessment NMA of 140 trials (23,383 participants) reported IGA as a binary outcome and ranked ruxolitinib 1.5% (OR 9.34, 95% CI 4.8, 18.18), delgocitinib 0.5% (OR 10.08, 95% CI 2.65, 38.37), delgocitinib 0.25% (OR 6.87, 95% CI 1.79, 26.33), very potent TCS (OR 8.34, 95% CI 4.73, 14.67), potent TCS (OR 5.00, 95% CI 3.80, 6.58), and tacrolimus 0.1% (OR 5.06, 95% CI 3.59, 7.13) as most effective, all with moderate confidence. Mild TCS, crisaborole 2%, pimecrolimus 1%, roflumilast 0.15%, difamilast 0.3% and 1%, and tacrolimus 0.03% were the least effective. In a sensitivity analysis of low risk of bias information (12 trials, 1639 participants), potent TCS, delgocitinib 0.5% and delgocitinib 0.25% were most effective, and pimecrolimus 1%, roflumilast 0.15%, difamilast 1% and difamilast 0.3% least effective. Class-level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors and were more effective than PDE-4 inhibitors; mild/moderate TCS were less effective than potent TCI and had similar effectiveness to mild TCI. Longer-term outcomes over 6 to 12 months showed a possible increase in effectiveness for pimecrolimus 1% versus vehicle (4 trials, 2218 participants) in a pairwise meta-analysis, and greater treatment success with mild/moderate TCS than pimecrolimus 1% (based on 1 trial of 2045 participants). Local adverse effects NMA of 83 trials (18,992 participants, 2424 events) reporting application-site reactions ranked tacrolimus 0.1% (OR 2.2, 95% CI 1.53, 3.17; moderate confidence), crisaborole 2% (OR 2.12, 95% CI 1.18, 3.81; high confidence), tacrolimus 0.03% (OR 1.51, 95%CI 1.10, 2.09; low confidence), and pimecrolimus 1% (OR 1.44, 95% CI 1.01, 2.04; low confidence) as most likely to cause site reactions. Very potent, potent, moderate, and mild TCS were least likely to cause site reactions. NMA of eight trials (1786 participants, 3 events) reporting pigmentation changes found no evidence for increased pigmentation changes with TCS and crisaborole 2%, with low confidence for mild, moderate or potent TCS and moderate confidence for crisaborole 2%. NMA of 25 trials (3691 participants, 36 events) reporting skin thinning found no evidence for increased skin thinning with short-term (median 3 weeks, range 1-16 weeks) use of mild TCS (OR 0.72, 95% CI 0.12, 4.31), moderate TCS (OR 0.91, 95% CI 0.16, 5.33), potent TCS (OR 0.96, 95% CI 0.21, 4.43) or very potent TCS (OR 0.88, 95% CI 0.31, 2.49), all with low confidence. Longer-term outcomes over 6 to 60 months showed increased skin thinning with mild to potent TCS versus TCI (3 trials, 4069 participants, 6 events with TCS).
CONCLUSIONS: Potent TCS, JAK inhibitors and tacrolimus 0.1% were consistently ranked as amongst the most effective topical anti-inflammatory treatments for eczema and PDE-4 inhibitors as amongst the least effective. Mild TCS and tapinarof 1% were ranked amongst the least effective treatments in three of five efficacy networks. TCI and crisaborole 2% were ranked most likely to cause local application-site reactions and TCS least likely. We found no evidence for increased skin thinning with short-term TCS but an increase with longer-term TCS.