用抗疟药治疗皮肤型红斑狼疮需要耐心

波士顿——在美国皮肤病学会夏季学术会议上，宾夕法尼亚大学赫尔希医学中心皮肤病科的Jennie T. Clarke博士指出，要提高抗疟药对皮肤型红斑狼疮(CLE)的疗效还有很长的路要走，并且需要极大的耐心。抗疟药是治疗CLE的有效药物，但仍有约1/3的患者经这类药物治疗后无应答。超过半数的CLE患者经羟氯喹单药治疗后获得应答。

一项纳入128例CLE患者的研究显示，约55%的患者经羟氯喹单药治疗后获得应答(Arch. Dermatol. 2011;147:1261-7)。无应答者在原有治疗基础上加用阿的平后，有2/3病情减轻。43%的患者在2个月后仍持续获得应答。该研究表明，经单一抗疟药治疗后无应答的患者，可在羟氯喹或氯喹基础上加用阿的平来获得应答。然而，有1/3的患者经抗疟药联合治疗后仍无法获得应答。Clarke博士表示，抗疟药起效较慢，因此在使用这类药治疗时应有足够的耐心，需在给药2~3个月后再评价疗效，并且还应让患者了解这点，否则他们易于变得沮丧和不依从治疗。

过去18个月进行的一些研究提示，剂量和依从性、疾病严重程度及吸烟状态是3种可能导致抗疟药治疗失败的原因。

羟氯喹的生物利用度和清除率依不同患者而有所不同。此外，不依从率约为10%。一项纳入300例CLE患者的法国研究显示，羟氯喹的中位血浆浓度与治疗反应有关(Arch. Dermatol. 2012;148:479-84)。完全应答患者的中位羟氯喹血浆浓度显著高于部分应答或治疗失败的患者。多因素分析显示，完全应答与较高的羟氯喹血浆浓度和无盘状狼疮病变有关。血浆浓度和治疗反应与实际的(而非理想的)按体重给药剂量相关。吸烟与血浆浓度无关。170例盘状红斑狼疮(DLE)亚组患者经羟氯喹治疗后应答不明显。30例(10%)患者的血浆羟氯喹浓度极低(＜200 ng/ml)，可视为不依从治疗。然而，尚需进行进一步研究，以确定最佳的羟氯喹血浆浓度及实际的按体重给药剂量的毒性的影响。

一项纳入200例DLE患者的研究显示，1/3(35%)的患者在羟氯喹治疗6个月后无应答。治疗反应不佳与疾病严重程度和并存的系统性红斑狼疮(SLE)相关。然而，治疗反应与存在细胞色素P450基因或吸烟无关(J. Invest. Dermatol. 2011;131:1981-6)。

一项纳入218例CLE或SLE皮肤病患者的研究显示，当前吸烟者的病情更严重且疾病相关生活质量更差。吸烟者接受抗疟药联合治疗的比例也较高。当前吸烟者对抗疟药的治疗反应优于既往吸烟者和从未吸烟者。然而，在使用抗疟药和免疫调节剂/抑制剂的情况下，吸烟者的治疗反应差于非吸烟者。该研究表明，抗疟药对吸烟者有效，尤其是病情较轻的吸烟患者。但是，与抗疟药治疗失败的非吸烟者相比，治疗失败的吸烟者的预后可能更差。

Clarke博士声明无相关经济利益冲突。

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By: KERRI WACHTER, Internal Medicine News Digital Network

BOSTON – The use of adjunctive therapy and a lot of patience may go a long way to improving the response of cutaneous lupus erythematosus to antimalarial agents, according to Dr. Jennie T. Clarke.

Antimalarials are the go-to treatment for cutaneous lupus erythematosus (CLE), yet roughly a third of patients do not respond, said Dr. Clarke, who spoke at the American Academy of Dermatology’s Summer Academy Meeting.

Findings from some recent studies shed light on how to improve that dismal response rate. In one of these trials involving 128 patients with CLE, researchers found that slightly more than half of patients who initiated treatment with hydroxychloroquine monotherapy were responders (55%) (Arch. Dermatol. 2011;147:1261-7). When quinacrine was added to the treatment regimen of the nonresponders, two-thirds experienced a lessening of their disease. Improvement continued beyond 2 months in 43%.

"With antimalarials remember that patience is important. [These agents] have a slow onset. You have to give the drugs for 2-3 months before assessing for efficacy. Patients need to know this because otherwise they’re going to become frustrated and noncompliant," said Dr. Clarke of the department of dermatology at Pennsylvania State University, Hershey.

The other important lesson from the study is about combination antimalarial therapy. Quinacrine can be added to either hydroxychloroquine or chloroquine to achieve improvement in patients who don’t respond to a single antimalarial agent.

However, roughly a third of patients don’t respond to a combination of antimalarials. Some research in the last 18 months has tried to identify which patients fail antimalarial treatment and why, in order to improve subsequent treatment. Three possible reasons have been identified: dosing and compliance, disease severity, and smoking status.

Bioavailability and clearance of hydroxychloroquine seems to vary by individual, she said. In addition, noncompliance is estimated to be about 10%. In a study of 300 CLE patients, French researchers found that the median blood concentration of hydroxychloroquine correlated with response (Arch. Dermatol. 2012;148:479-84). Specifically, the median blood hydroxychloroquine concentration was significantly higher in patients with complete remission compared with those with either partial remission or treatment failure. Findings from the multivariate analysis showed that complete remission was associated with higher blood hydroxychloroquine concentrations and the absence of discoid lesions.

Concentration and response were correlated with actual rather than ideal body weight dosing. Smoking was not found to be related to concentration, and the subset of 170 patients with discoid lupus erythematosus (DLE) was less responsive to hydroxychloroquine.

Thirty patients (10%) had very low blood hydroxychloroquine concentrations (less than 200 ng/mL) and may be considered nonadherent to the treatment regimen, Dr. Clarke noted. However, additional study is needed to determine the optimal blood concentration of hydroxychloroquine and the impact of toxicity with actual weight-based dosing rather than ideal body weight dosing.

In another study, researchers assessed the clinical and pharmacogenic influences of disease severity on response to blood concentration of hydroxychloroquine (J. Invest. Dermatol. 2011;131:1981-6). They assessed 200 patients with DLE. Slightly more than a third (35%) of patients had not responded to hydroxychloroquine at 6 months. Poor response was associated with disease severity and concomitant systemic lupus erythematosus (SLE). However, response was not associated with the presence of cytochrome P450 genotype or smoking.

It has been long held medical dogma that smoking lessens patients’ response to antimalarial drugs. The impact of smoking in patients with CLE was assessed directly in another paper (Arch. Dermatol. 2012;148:317-22). The researchers included 218 patients with CLE or SLE with skin disease. They found that current smokers had more severe disease and poorer disease-related quality of life. Smokers were also more likely to receive combination antimalarial therapy. Current smokers responded better to antimalarials than past or never smokers. However, smokers responded worse than nonsmokers if antimalarials and immunomodulator/suppressives were required.

"This tells us that antimalarials can be effective for smokers, particularly in those with more mild disease. But we need to remember that smokers who don’t respond are likely going to have poorer outcomes than nonsmokers who don’t respond to antimalarials."

Dr. Clarke reported having no relevant financial conflicts.