针对红斑痤疮的新疗法

旧金山——加州大学旧金山分校的Kanade Shinkai医生在太平洋皮肤病学会(PDA)年会上指出，关于红斑痤疮的治疗，将迎来更美好的前景。“两种激动人心的新治疗”似乎可以改变这种治疗困难疾病的临床实践，目前研究者仍在继续收集更多关于其应用的数据。


Kanade Shinkai医生

使用利福昔明抑制小肠细菌过度生长和8月份刚刚通过核准作为首个治疗红斑痤疮红斑的局部用药的溴莫尼定新剂型的治疗红斑痤疮方案的初步数据令人鼓舞。

这一策略起源于2008年的一项研究，该研究显示，113例红斑痤疮患者中有52例(46%)伴有小肠细菌过度生长(SIBO)，而60例健康的匹配对照中仅有3例(5%)伴有SIBO。使用抗生素利福昔明（一种与利福平同类的药物）400 mg每日3次，用药10天，治疗SIBO，结果45例SIBO得到根治的患者中有35例(78%)红斑痤疮消失。其中96%的患者维持红斑痤疮消失长达9个月。2例患者的红斑痤疮与SIBO同时复发(Clin. Gastroenterol. Hepatol. 2008;6:759-64)。更近期的一项初步研究显示，63例红斑痤疮患者中的32例(51%)伴有SIBO，而一般人群中的30例对照受试者中仅有7例(23%)伴有SIBO。在28例因SIBO服用利福昔明的患者中，46%的患者红斑痤疮消失，25%发生中度改善，11%发生轻度改善。18%的患者红斑痤疮未见改善(J. Am. Acad. Dermatol. 2013;68:875-6)。在这项研究中，皮肤科医生确认了多数红斑痤疮病例。研究使用一种阳性乳果糖/葡萄糖呼吸测试作为诊断SIBO的替代指标，这是一种较标准诊断方法空肠抽吸侵入性更小的方法。需要进行使用空肠抽吸诊断方法的更大规模的双盲研究，“以证实这是一种有价值的治疗，”Shinkai医生说。

研究者推测，SIBO可能通过增加肿瘤坏死因子-α、抑制白细胞介素-17或增加1型T辅助细胞通路基因表达，以调控细胞因子，并促使发生皮肤炎症。机械地讲，肠道可能诱导分子模拟，从而导致这些细胞因子触发的肠道外疾病，Shinkai医生说：“红斑痤疮的治疗可能非常困难。这至少是我们可以尝试的一条路径，”她说，伴有更多GI症状的红斑痤疮患者“将是我们采用利福昔明治疗的目标人群。”

对红斑痤疮治疗方案的另一追加药物为新的0.33%的局部使用溴莫尼定凝胶(Mirvaso)，这一药物于2013年8月经美国食品药品管理局核准用于治疗成人红斑痤疮的面部红斑。每克凝胶含酒石酸溴莫尼定5 mg，相当于溴莫尼定游离碱3.3 mg，销售该药物的高德美公司声称。“鉴于当前我们对红斑痤疮患者的建议，即避免触发因素（日光暴露、辛辣食物、灼热液体）或考虑激光治疗（由于保险问题，对于很多患者无法选择），这是一个非常重要的突破，”她说。溴莫尼定是一种高选择性α2-肾上腺素能激动剂，对血管的收缩作用很强。由于其已长期应用于青光眼治疗，故安全性和疗效特性均已明确，但局部用凝胶是一种新的剂型。

本项核准是基于高德美公司资助的在总共391例患者中进行的关于不同剂量凝胶的2项关键试验，该研究显示剂量依赖性红斑减少12小时，且临床医生、患者和色度仪评定的红斑有二度改善(Br. J. Dermatol. 2012;166:633-41)。这种药物起效很快，并且耐受性良好，Shinkai医生说。停用药物可导致一种快速耐受，这种快速耐受也见于其他用于治疗鼻腔或结膜充血的-肾上腺素能药物，停用药物可加重红斑或水肿。研究中的2例患者发生轻微、一过性眼内压降低，可能为无意中使凝胶进入眼内所致，她说。两项研究均为期较短，随访4周。

Shinkai医生认为，目前断言这种治疗的效益仍为时过早，尚需更多关于溴莫尼定长期应用治疗红斑痤疮的红斑的数据。“但我认为这是一种相当激动人心的新进展”，是对现有的少数治疗工具的有益补充。

Shinkai医生披露无相关利益冲突。

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By: SHERRY BOSCHERT, Internal Medicine News Digital Network

SAN FRANCISCO – Things are looking rosier for the treatment of rosacea, according to Dr. Kanade Shinkai.

"Two exciting new treatments" are likely to change clinical practices around this difficult-to-treat disease while researchers continue to gather more data on their use, she said at the annual meeting of the Pacific Dermatologic Association.
 
Dr. Shinkai said she was encouraged by preliminary data on treating rosacea indirectly by using off-label rifaximin for small intestinal bacterial overgrowth and by a new formulation of brimonidine approved in August as the first topical agent for the erythema of rosacea.

The GI approach looks promising enough to incorporate into her practice, said Dr. Shinkai of the University of California, San Francisco.

That strategy grew out of a 2008 study showing that 52 (46%) of 113 patients with rosacea had small intestinal bacterial overgrowth (SIBO) compared with 3 (5%) of 60 healthy matched controls. Treating SIBO with the antibiotic rifaximin (a cousin of rifampin) at 400 mg thrice daily for 10 days cleared rosacea in 35 (78%) of the 45 patients in whom SIBO was eradicated. Cleared rosacea remained clear for up to 9 months in 96% of patients. In two patients, both rosacea and SIBO recurred (Clin. Gastroenterol. Hepatol. 2008;6:759-64).

Investigators hypothesized that SIBO might modulate cytokines by increasing tumor necrosis factor–alpha, suppressing interleukin-17, or increasing the T helper cell type 1 pathway gene to drive skin inflammation. Mechanistically, the gut could be inducing molecular mimicry that results in extraintestinal disease due to these cytokine triggers, said Dr. Shinkai.

A more recent pilot study showed that 32 (51%) of 63 patients with rosacea had SIBO compared with 7 (23%) of 30 control subjects in the general population. Among 28 patients who took rifaximin for their SIBO, rosacea cleared in 46%, moderately improved in 25%, and mildly improved in 11%. No improvement was seen in 18% (J. Am. Acad. Dermatol. 2013;68:875-6).

"Rosacea can be very difficult to treat. This is at least one avenue that we can ask about," she said. Patients with rosacea who have more GI symptoms "will be the ones that I’ll target with rifaximin."

Most cases of rosacea in the study were confirmed by dermatologists. The studies used a positive lactulose/glucose breath test as a surrogate for diagnosing SIBO, a less-invasive strategy than the standard for diagnosis: jejunal aspirate. Larger double-blind studies that include jejunal aspirates probably will be needed "to really prove that this is a worthy treatment," Dr. Shinkai said.

The other addition to the regimen for rosacea is the new 0.33% topical brimonidine gel (Mirvaso), approved by the Food and Drug Administration in August 2013 for the treatment of the facial erythema of rosacea in adults. Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base, according to Galderma, which markets the drug.

"I think that’s a very important breakthrough considering what we tell patients now for erythema, which is to avoid their triggers (sun exposure, hot spicy foods, hot liquid) or to consider laser therapy, which is not an option for many patients because of the insurance issue," she said.

Brimonidine is a highly selective alpha2-adrenergic agonist that is very vasoconstrictive. The drug has a known safety and efficacy profile from its long-term use as a treatment for glaucoma, but the topical gel is a new formulation.

Approval was based on two Galderma-funded pivotal trials of various doses of the gel in a total of 391 patients, which showed dose-dependent reductions in erythema for 12 hours and a two-grade improvement in erythema ratings by clinicians, patients, and Chroma Meter (Br. J. Dermatol. 2012;166:633-41).

The drug was fast acting and well tolerated, Dr. Shinkai said. Stopping the medication did cause a kind of tachyphylaxis seen with other alpha-adrenergics used to treat nasal or conjunctival congestion, where stopping the drug increased erythema or edema. Two patients in the studies developed mild, transient decreases in intraocular pressure, probably a result of inadvertently getting the gel in the eye, she said. Both studies were short, with 4 weeks of follow-up.

"I think the jury is still out" until more data become available on long-term use of brimonidine for erythema in rosacea. "However, I think this is a really exciting new development" because it adds to the few tools available for treatment, she said.

Dr. Shinkai reported having no relevant financial disclosures.