单克隆抗体药物Efalizumab(商品名Raptiva，Genentech/Xoma)治疗银屑病(牛皮癣)的分子基础。

　　银屑病是一种常见的皮肤病，以红色或粉红色且带有白色或银色鳞片的增长性皮肤损伤为特征。现有资料表明，白细胞(主要是T细胞)在表皮部分的渗入活动是引起和维持银屑病症状存在的主要驱动力，而在此过程中涉及许多细胞间的黏附分子，其中包括属于整合素(integrin)家族的淋巴细胞功能相关抗原-1(LFA-1)。LFA-1通过其a亚基的I domain与它的最重要的配体——细胞间黏附分子-1(ICAM-1)的domain 1结合，参与介导许多免疫过程。

　　Efalizumab是一种针对LFA-1的a亚基的人源化单克隆抗体药物，可以通过阻止LFA-1与ICAM-1的结合进而抑制白细胞的活动。该抗体药物于2002年通过FDA批准，是目前治疗牛皮癣的最有效的药物之一。丁建平课题组的李胜同学等运用结构生物学和生物化学的方法，研究了Efalizumab的Fab片断和该片断与LFA-1的a亚基的I domain的复合物的晶体结构以及抗原—抗体相互作用的性质。通过对复合物的结构分析以及与文献中生化数据的比较，鉴定了Efalizumab的抗原决定表位(epitope)。

　　结构分析显示，在复合物结构中I domain处于非激活状态，Efalizumab在I domain上的抗原决定表位不同于ICAM-1的结合位点。进一步通过与已报道的LFA-1 I domain/ICAM-1复合物的结构比较，发现Efalizumab与LFA-1 I domain的结合，会导致Fab的轻链与ICAM-1的domain 2产生空间位置的重叠，从而阻碍了ICAM-1与LFA-1的结合，并进一步抑制了LFA-1的活性。这些结果在分子水平上揭示了Efalizumab对LFA-1的活性产生抑制作用的分子机制，并合理解释了已有的生物化学和免疫学数据。基于该研究结果，研究人员提出了通过对Efalizumab进行定点突变、研发具有更高特异性和更强亲和力的抗体药物的策略，同时依据该抗体药物与小分子药物具有不同作用位点的结果，提出了将Efalizumab与其他小分子药物联合应用以达到更佳治疗效果的方案。这些研究结果对于抗牛皮癣的抗体药物的研发和临床治疗具有重要的指导意义。

New Onset Psoriatic Arthritis Reported in Psoriasis Patients Treated with Efalizumab

The T-cell inhibitor efalizumab (Raptiva)hasdemonstrated efficacy in the treatment of moderateto severe plaque psoriasis.  However, ithasnotdemonstrated efficacy for the treatment of psoriatic arthritis and, in one study, was associated with worsening ofarthritis symptoms.  Only a minority of individuals withpsoriasis have a concomitant inflammatory arthritis,makingtherapy with efalizumab an option for the treatment ofalargenumberofpsoriasispatientswhohavenoarticularinvolvement.  Here, Viguier et al (Arthritis Rheum 2008; 6(58):1796) report a case series of psoriasis patients with new-onset psoriatic arthritis temporally associated with therapy with efalizumab.

Methods
Members of 12 dermatology departments throughout France known to prescribe biologic therapy for psoriasis were queried for patients with inflammatory arthritis after initiating efalizumab therapy.  Follow-upquestionnaires were then sent to patients and practitioners regarding past history of psoriasis and treatment, current and past articular and extra-articular signs and symptoms of psoriatic arthritis, and outcomes of arthritis symptoms with withdrawal or continuation of efalizumab.  ANA, RF, anti-CCP, and HLA-B27 were measured.

Results
Sixteen patients were identified with inflammatory arthritis symptoms after beginning efalizumab for psoriasis.  Patients were between 28 and 60 years of age (mean age 50 years) with an average duration of psoriasis of 16 years (range 3 to 37 years).  Only 1 patient had a family member with ahistoryofinflammatory arthritis.  Arthritis symptoms began a median of 11 weeks after initiation of efalizumab (range 1 to 48 weeks).  Most commonly affected jointswere,indescending order of frequency, knees, DIPs, spine, enthesitis, and dactylitis.  Almost half of patients demonstrated both axial and peripheral symptoms.  No patients had high titer RF, anti-CCP, or ANA.  Only one was HLA-B27 positive.  Only onepatienthadapasthistoryofinflammatory joint involvement.

The severity ofarthritissymptomsprompteddiscontinuation of efalizumab in 11 patients. Mostofthesehadimprovement in symptoms after withdrawal, although NSAIDs and other DMARDs were required in all but one.  Two were treated with TNF inhibitors, with improvement, due topersistent disease activity after withdrawal.  Two patients had a re-challenge with efalizumab, both with relapse of arthritis within a time frame similar to initial onset.

An estimated 450 psoriasis patients received efalizumab in France over the time-period of the study, resulting in an estimated incidence of de novo psoriaticarthritis of 3.5%.

Conclusions
New onset psoriatic arthritis appears to be temporally associated with efalizumab therapy in patients with psoriasis.

Editorial Comment
Although still a rare occurrence,patientsandprescribers of efalizumab should be aware of this potential side-effect.  Because some patients with psoriasis will go on to develop psoriatic arthritis during the course of their disease, often after years to decadesofpsoriasis, it is impossible to definitively determine whether the onset of inflammatory arthritis was causally related to the drug in every case, or the natural history of their underlying disease. However,theclosetemporalrelationship in many, but not all, cases and re-emergence of symptoms with re-challenge is supportive of a causal relationship in some patients.  Further experience with the drug may aid in identifying risk factors for incident psoriatic arthritis, such that the drug could be avoided in those at highest risk.  In addition, these findingsmaysuggest clues to the pathogenesis and inter-relation between the mechanisms underlying skin psoriasis and psoriatic arthritis.