磷酸二酯酶4抑制剂治疗特应性皮炎的研究进展

目前特应性皮炎的治疗主要是外用糖皮质激素(激素)和钙调磷酸酶抑制剂,重症患者可以联合口服免疫抑制剂和光疗。尽管糖皮质激素外用制剂的疗效显著且不良反应少,但患者的恐激素心理限制了其临床应用。临床需要一种更安全、不良反应更小的外用非激素类抗炎药物来治疗特应性皮炎。磷酸二酯酶4(phosphodiesterase 4,PDE4)抑制剂通过降解环磷酸腺苷参与调控促炎性细胞因子的释放。特应性皮炎患者炎性细胞中PDE4的活性增加,导致促炎性细胞因子和趋化因子的产生增加。靶向PDE4治疗可减少促炎症递质的产生。局部外用和口服PDE4抑制剂均已被证实安全性较好。2%crisaborole软膏,已被美国食品和药物管理局批准用于治疗2岁以上儿童和成人特应性皮炎。其他PDE4抑制剂正处于临床试验阶段,已经公布的有效性和安全性结果提示其用于特应性皮炎的治疗具有良好前景。     

外用磷酸二酯酶4抑制剂在特应性皮炎中的研究进展

特应性皮炎(AD)是一种反复发作的炎症性皮肤病,患者往往有剧烈瘙痒,严重影响生活质量。在过去,AD的治疗主要是外用糖皮质激素或钙调神经磷酸酶抑制剂。以上药物在治疗的同时常有一些显著的不良反应和局限性。因此,需开发一种更加安全有效且副作用小的药物。环核苷酸磷酸二酯酶4(phosphodiesterase 4, PDE4)是炎症细胞和免疫细胞中水解环磷腺苷(cAMP)的关键细胞内酶。AD患者白细胞中PDE4活性增加可使cAMP降解,导致促炎症因子的激活。因此,靶向抑制PDE4可以下调促炎症因子的产生,实现AD的治疗。PDE4外用制剂可以避免口服药物及传统外用药引起的不良反应,提高安全性和有效性。本文就目前已发表的相关文献对外用PDE4抑制剂治疗特应性皮炎作一综述。     

JAK抑制剂治疗斑秃的研究进展

【摘要】 斑秃是一种突然发生的局限性脱发,严重者可进展为全秃或普秃。目前认为斑秃是一种具有遗传背景的器官特异性自身免疫性疾病,毛囊免疫赦免结构的破坏是重要的发病机制。目前,斑秃的治疗方法有口服、外用、肌内或局部皮损内注射糖皮质激素、外用米诺地尔酊等,但仍有一部分患者治疗无效。近年来,国外开展了很多有关JAK抑制剂治疗斑秃的临床试验。研究显示,在采用口服JAK抑制剂治疗的患者中,约半数中重度斑秃患者在治疗后毛发几乎完全长出,疗效较明显。也有报道外用鲁索替尼治疗斑秃,但疗效不一。尽管部分患者在停药后复发或是在治疗过程中出现感染等不良反应,JAK抑制剂确实为有效治疗中重度斑秃提供了一种选择。     

激光与光疗治疗斑秃的研究进展

斑秃是一种常见的、炎性的、非瘢痕性脱发。发病机制目前尚不清楚,可能与T淋巴细胞与毛囊抗原(自身抗原)相互作用、环境、自身免疫性疾病等因素相关。现有的治疗方法有糖皮质激素、米诺地尔搽剂、外用刺激物、致敏剂、免疫抑制剂等。以上疗法在起效的同时常伴有一些不良反应,激光和光疗作为新的治疗方法,能有效治疗并降低不良反应。本综述的目的在于为临床医师提供激光和光疗治疗斑秃的临床总结。     

小分子靶向药物在皮肤病领域的研究进展

小分子靶向药物作为新型药物,正处于治疗皮肤病临床试验研究前沿,包括Janus激酶(JAK)抑制剂,磷酸二酯酶(PDE)抑制剂和蛋白激酶C(PKC)抑制剂等。为进一步提高疗效,减少不良反应和治疗成本,阻断特异性细胞因子作用的小分子靶向药物逐步用于治疗部分难治性皮肤病。本文就小分子靶向药物在皮肤病领域中的研究进展进行综述。     

外用糖皮质激素的合理应用

外用糖皮质激素是治疗皮肤病最有用的药物之一,目前有很多外用糖皮质激素可供选择,他们在剂型和强度上有较大差异.外用糖皮质激素成功治疗取决于正确的诊断、选择合适剂型和强度的药物、用药的频率、剂量和疗程,以及不良反应的预防.明确诊断之后,应根据外用糖皮质激素的作用机制选择药物,外用糖皮质激素可用于治疗具有增生性、炎症性和与免疫相关的皮肤病,也能缓解瘙痒和烧灼症状,但一般情况下不用于感染性疾病.虽然外用糖皮质激素在临床上普遍使用,但目前循证医学证据表明,治疗有效的疾病有银屑病、白癜风、特应性皮炎、湿疹、急性放射性皮炎、硬化性苔藓等[1-5],证据有限的疾病有黄褐斑、慢性特发性荨麻疹和斑秃[4-6].     

JAK抑制剂治疗儿童斑秃的研究进展

斑秃(AA)是一种常见的非瘢痕性脱发,儿童斑秃预后不佳、病情易反复,可严重影响患者及家长的心理健康和生活质量。近年来,人们逐渐发现酪氨酸蛋白激酶(JAK)/信号转导与转录激活因子(STAT)信号通路在斑秃的发病机制中起着重要作用。目前已有多篇病例报告和小型临床试验报道JAK抑制剂治疗儿童斑秃的有效性及安全性,因此JAK抑制剂对于儿童中重度斑秃的治疗可能会成为一种新的选择。     

斑秃的外用药物治疗

外用药物在斑秃治疗中具有重要作用,本文就外用糖皮质激素、致敏剂二苯基环丙烯酮和斯夸酸二丁酯、蒽林、米诺地尔、比马前列素、维A酸、贝沙罗汀、卡泊三醇、辣椒碱、壬二酸、大蒜凝胶和洋葱汁治疗斑秃的在斑秃中的应用进行综述。     

特殊人群使用PDE-5抑制剂的效果观察及治疗结局的反思

目的评价特殊人群使用5型磷酸二酯酶(PDE-5)抑制剂的效果以及对目前勃起功能障碍(ED)治疗现状的反思。方法选择2009年7月至2018年6月十堰市人民医院男科以"勃起功能障碍"为主诉就诊的95例患者为研究对象,从中筛选以下4类患者:长期使用抗精神病药物者(APP)43例、木讷者(SRP)37例、同性恋者(HSP)10例和无性恋者(ASP)5例,记录他们的病史特点,随机使用PDE-5抑制剂共14周,在出院当天和出院后12周评估治疗效果。观察指标包括:国际勃起功能指数评分5(IIEF-5)、性活动日志(SEP)等,同时评估药物的安全性和耐受性。结果阴茎夜间勃起测试(NPT)结果显示存在器质性ED患者:APP中有10例,SRP中有2例,ASP中有1例。APP患者IIEF-5评分出院当天均值[(16.00±5.06)分]高于入院当天[(7.39±1.70)分],其差异具有统计学意义(P0.05)。SRP患者IIEF-5评分出院当天均值[(10.35±3.73)分]高于入院当天[(6.89±1.52)分],其差异具有统计学意义(P0.05)。HSP和ASP评分在出院当天和入院当天比较,其差异均无统计学意义(均P 0.05)。出院后12周,所有四组患者IIEF-5评分与出院当天评分相比,组内差异均无统计学意义(均P 0.05)。SEP-2(能否插入阴道?)在APP患者中出院当天(39.5%)和出院后12周(46.5%)与入院当天(7%)相比,其差异具有统计学意义(P0.05)。在SRP患者中出院当天(48.7%)和出院后12周(56.8%)与入院当天(5.4%)相比,其差异具有统计学意义(P0.05)。SEP-3(勃起时间能否完成性交?)在APP患者中出院当天(27.9%)和出院后12周(34.9%)与入院当天(0%)相比,其差异具有统计学意义(P0.05)。在SRP患者中出院当天(10.8%)和出院后12周(13.5%)与入院当天(0%)相比,其差异具有统计学意义(P0.05)。而HSP和ASP完成性交的成功率极低。西地那非的不良反应主要表现为视觉异常,出现蓝视、绿视,其次为颜面潮红、头痛,均与剂量有明显关系;他达拉非的不良反应主要表现为肌痛:均不影响药物的使用。结论在PDE-5抑制剂有效的APP和SRP患者中,建议长期小剂量或超低剂量使用,不良反应的出现不影响药物的使用;无效者不推荐继续使用。HSP和ASP患者不推荐使用PDE-5抑制剂。将ED作为慢性病管理,应当让患者明白,坚持长期用药也不能达到治愈的可能,但可以做到随时使用、随时有效、随时停用,根据自身经济因素、文化层次、性生活频次、性爱的场合、性交对象、女方反应等因素综合考虑。     

JAK抑制剂治疗儿童重症斑秃5例

目的观察JAK抑制剂治疗5例儿童重症斑秃及合并甲改变患者的疗效。方法收集2020年1月至2022年4月于北京儿童医院就诊的5例重症斑秃患儿, 予JAK抑制剂(托法替布或巴瑞替尼)口服治疗, 采用斑秃严重程度评估工具(SALT)评估治疗12、24、36、48周秃发改善程度。对其中3例合并甲改变的重症斑秃患儿, 采用改良的甲银屑病指数评分评估治疗前后甲病的改善程度。治疗过程中同时监测不良反应。结果 5例重症斑秃患儿, 年龄2 ～ 11岁, 病程5 ～ 120个月, JAK抑制剂疗程24 ～ 48周。治疗12周, 2例患儿SALT改善率达SALT50;治疗24周, 3例达SALT95, 1例达SALT75后自行停药;治疗36周, 3例达SALT99, 开始减半量治疗;治疗48周, 4例SALT改善率分别为SALT99、SALT83、SALT31、SALT0, 其中2例为减半量治疗1 ～ 2个月出现反复并逐渐加重。3例合并甲改变的患儿, 治疗12周后手指甲严重程度指数改善率分别为67.5%、45.4%和25%, 足趾甲分别为42.5%、71.4%和5%;治疗48周, 这3例手指甲改善率分别为1...     

Circumscribed alopecia areata incognita

The characteristic lesion of alopecia areata is a smooth bald patch on the scalp. When there is no bald surface it is called alopecia areata incognita. To date, all cases of alopecia areata reported as so‐called ‘incognito’ have shown a diffuse involvement of the scalp as in acute telogen effluvium. Recently, we have observed two patients who showed localised hair thinning of the scalp without bald spots. Histopathologically, the lesions were typical of alopecia areata with peribulbar lymphocytic infiltrates. The response to corticosteroid treatment and its clinical course were also compatible with alopecia areata.     

Severe alopecia areata treated with systemic corticosteroids

Background Treatment of severe alopecia areata is difficult, and most efforts to successfully treat this condition have been disappointing. Systemic corticosteroids have been demonstrated as an effective treatment of severe alopecia areata. Methods Eighteen patients with alopecia areata (extensive patchy and totalis universalis types) were treated with systemic corticosteroids. Results Satisfactory hair regrowth was achieved in seven patients (38.9%). Hair fall subsequently occurred in all of these patients on discontinuation or tapering of corticosteroid therapy. Conclusions Systemic corticosteroid therapy does not prevent the spread or relapse of severe alopecia areata and, when complete regrowth is obtained, it is rarely maintained off therapy.     

Comparison of High-Dose Corticosteroid Pulse Therapy and Combination Therapy Using Oral Cyclosporine with Low-Dose Corticosteroid in Severe Alopecia Areata

BackgroundSevere alopecia areata (AA) is resistant to conventional treatment. Although systemic oral corticosteroids are an effective treatment for patients with severe AA, those drugs have many adverse effects. Corticosteroid pulse therapy has been introduced to increase therapeutic effects and reduce adverse effects. However, the treatment modality in severe AA is still controversial.ObjectiveTo evaluate the effectiveness of corticosteroid pulse therapy in patients with severe AA compared with treatment with oral cyclosporine with corticosteroid.MethodsA total of 82 patients with severe AA were treated with corticosteroid pulse therapy, and 60 patients were treated with oral cyclosporine with corticosteroid. Both groups were retrospectively evaluated for therapeutic efficacy according to AA type and disease duration.ResultsIn 82 patients treated with corticosteroid pulse therapy, 53 (64.6%) were good responders (>50% hair regrowth). Patients with the plurifocal (PF) type of AA and those with a short disease duration (≤3 months) showed better responses. In 60 patients treated with oral cyclosporine with corticosteroid, 30 (50.0%) patients showed a good response. The AA type or disease duration, however, did not significantly affect the response to treatment.ConclusionCorticosteroid pulse therapy may be a better treatment option than combination therapy in severe AA patients with the PF type.     

Analysis of the expression of cutaneous lymphocyte-associated antigen on the peripheral blood and cutaneous lymphocytes of alopecia areata patients

Alopecia areata has been reported to be accompanied by abnormal autoimmune dysfunction. We examined the expression of cutaneous lymphocyte-associated antigen (CLA), which is a skin-specific lymphocyte homing receptor, in the peripheral blood lymphocytes and skin of patients with alopecia areata. In the patients' peripheral blood, the percentage of CLA-positive CD4+ or CD8+ lymphocytes, was significantly higher than that of normal controls. The patients with severe or progressive alopecia areata showed a much higher CLA-positivity compared to patients recovering from the disease. A chronological study showed that the percentage of CLA-positive peripheral blood lymphocytes, CD4 + or CD8 + lymphocytes decreased in parallel with the patients' good clinical course. The CLA-positivity in peripheral blood lymphocytes, CD4+ or CD8+ lymphocytes of patients with alopecia areata who did not respond to oral corticosteroid therapy remained higher than in those who responded well to the treatment. In the affected scalp skin, many infiltrating lymphocytes around the hair follicles, which were CD4+ or CD8+ lymphocytes, expressed CLA. These findings suggest that the CLA-positivity correlates with clinical activity and that CLA-positive CD4+ or CD8+ lymphocytes may play an important role in alopecia areata.     

Treatment of alopecia areata with 308-nm excimer lamp

Alopecia areata is considered to be a T-cell mediated autoimmune disorder. The 308-nm excimer lamp is thought to be capable of inducing T-cell apoptosis in vitro, suggesting that the lamp might be effective for the treatment of alopecia areata. We examined the effectiveness of the 308-nm excimer lamp for the treatment of alopecia areata. We recruited three patients with single alopecia areata lesions that were resistant to conventional treatment. The lesions were exposed to a 308-nm excimer lamp at 2-weekly intervals. Hair regrowth was observed in all three patients after approximately 10 treatment sessions. Our study showed that exposure to the 308-nm excimer lamp effectively induced hair regrowth in solitary alopecia areata lesions. Apart from erythema, there were no significant adverse effects. Therefore, we suggest that it may be considered as a treatment modality for recalcitrant alopecia areata.     

The effect of the PDE-4 inhibitor (cipamfylline) in two human models of irritant contact dermatitis

BACKGROUND: New therapeutic approaches have to be considered in the treatment of irritant contact dermatitis (ICD). Recently, phosphodiesterase 4 (PDE-4) inhibitors have been introduced as nonsteroidal, antiinflammatory agents. These agents inhibit the secretion of the cytokines thought to be involved in the pathogenesis of ICD. We investigated the effect of a new selective PDE-4 inhibitor (cipamfylline) in human models using single and repeated exposures to an irritant in a blind, randomized pilot study with healthy volunteers. We compared the effect of cipamfylline ointment with a strong corticosteroid (betamethasone-17-valerate) and with a placebo ointment. METHODS: Ten volunteers were patch tested at four investigation sites with sodium dodecyl sulphate (1%) for 24 h. In a model that simulates chronic damage, 11 volunteers were patch tested with sodium dodecyl sulphate (0.2%) for 4 h daily for four consecutive days. The investigation sites were treated once a day with the above-mentioned agents. One site was left untreated. We used erythema scoring, measurements of transepidermal water loss (TEWL) and several immunohistochemical markers for epidermal proliferation and differentiation. RESULTS: Repeated application revealed that betamethasone-17-valerate caused a statistically significant reduction in erythema and TEWL compared to cipamfylline and placebo. We also observed a significant suppression of proliferating cells and cytokeratin 16 expression at sites treated with betamethasone compared to the other sites. In the model for acute ICD, no significant differences were seen between the investigated sites. CONCLUSIONS: Our results show that betamethasone-17-valerate may modulate the response in ICD. In this human model of ICD we could not confirm the efficacy of cipamfylline. Clinical studies are needed before the effect of PDE-4 inhibitors in ICD can be refuted with certainty.     

Systemic treatments for alopecia areata: A systematic review

A range of systemic treatments are used for alopecia areata with variable evidence supporting efficacy. In this systematic review, we evaluated the evidence surrounding systemic treatments for alopecia areata, alopecia totalis and alopecia universalis. A systematic search was conducted of the peer-reviewed literature published between 1946 and March 2018 via Medline, Embase, Amed, the Cochrane Central Register of Controlled Trials, PsychINFO and Lilacs. All randomised controlled trials (RCTs) that evaluated the effectiveness of systemic treatments for individuals with alopecia areata, totalis or universalis were included. Sixteen studies were included with a total of 768 participants. We found eight placebo-controlled RCTs, three RCTs comparing two systemic treatments and five RCTs comparing three treatments. A total of 15 different systemic therapies were investigated. The most frequently investigated therapy was oral prednisolone pulse therapy and oral inosiplex. There was significant variability in the definition of treatment success. No study evaluated the impact of pharmacotherapy on quality of life using complete quantitative quality of life instruments. Adverse events were reported in 13 studies and were corticosteroid related or otherwise well tolerated. Relapse rates were considerable in the four studies that reported this outcome. There is currently no specific systemic therapy that is supported by robust body of evidence from RCTs. The current evidence suggests efficacy of oral prednisolone pulse therapy and oral inosiplex. Evidence does not support the use of oral zinc sulphate, alefacept and efalizumab. Future RCTs should be adequately powered and employ clearly defined clinical response endpoints to allow future meta-analyses.     

DPCP for the treatment of alopecia areata

Topical immunotherapy with diphencyprone (DPCP) for the treatment of severe alopecia areata has been used since 1983 and is felt to be the treatment of choice by many dermatologists. Although there have been no major side effects reported since its initial use, there remain some unknowns regarding its safety. Because DPCP has at least a 40% success rate for cosmetically acceptable regrowth in extensive alopecia areata, its availability is an important matter for patients with alopecia areata.     

2‐deoxy D‐glucose treatment does not elicit a hair growth response in alopecia areata

2‐deoxy D‐glucose (2DG) was tested for efficacy in treating alopecia areata using the C3H/HeJ skin graft model. 2DG has proven to be efficacious in treatment of various mouse models of autoimmunity with minimal serious side effects noted. This agent has been shown to normalize abnormally activated T‐cell populations while also preventing cell surface expression of NKG2D; key factors defining alopecia areata disease progression. Daily oral ingestion of 2DG via drinking water to mice with patchy or diffuse alopecia areata for 16 weeks failed to prevent expansion of alopecia or cause regrowth of hair in treated mice. Histologically, there were no differences between treated and control groups. These results indicate that, while 2DG is effective for some autoimmune diseases, it was not efficacious for the cell‐mediated autoimmune mouse disease, alopecia areata.     

Management of hair loss diseases

The treatment of hair loss diseases is sometimes difficult because of insufficient efficacy and limited options. However, recent advances in understanding of the pathophysiology and development of new remedies have improved the treatment of refractory hair loss conditions. In this article, an update on the management of hair loss diseases is provided, especially focusing on recently reported therapeutic approaches for alopecia areata (AA). An accurate diagnosis is indispensable to optimize treatment. Dry dermoscopy represents new diagnostic techniques, which could enable the differentiation of barely indistinguishable alopecias, e.g. AA and trichotillomania. An organized scalp biopsy adopting both vertical and transverse sectioning approaches also provides a deep insight into the pathophysiology of ongoing alopecias. Among various treatments for AA, intraregional corticosteroid and contact immunotherapy have been recognized as first-line therapies. However, some AA cases are refractory to both treatments. Recent studies have demonstrated the efficacy of pulse corticosteroid therapy or the combination of oral psoralen ultraviolet A therapy and systemic corticosteroids for severe AA. Previous clinical observations have suggested the potential role of antihistamines as supportive medications for AA. Experimental evaluation using AA model mice further supports their effectiveness in AA treatment. Finasteride opens up new possibilities for the treatment of androgenetic alopecia. For androgenetic alopecia patients refractory to finasteride, the combination of finasteride with topical minoxidil or the administration of dutasteride, another 5 alpha-reductase inhibitor, may provide better outcomes. Scarring alopecia is the most difficult form of hair loss disorder to treat. The bulge stem cell area is destroyed by unnecessary immune reactions with resultant permanent loss of hair follicle structures in scarring alopecia. Currently, treatment options for this hair loss disorder are extremely limited. The development of effective therapies for this form of intractable alopecia represents an important issue to be resolved.