总结：虽然这是一篇讲PSC发病机制的综述，最后还是对其治疗的研究进展进行了一个简短的总结，毕竟机制研究的目的就是为了更好的治疗。不过，本节内容总结的也只是很普遍的一些治疗策略：最常用的治疗方法是UDCA，各种免疫抑制剂治疗效果欠佳，比如糖皮质激素、他克莫司、硫唑嘌呤、甲氨蝶呤等。也提了一句自体造血干细胞移植和自体Treg细胞移植治疗。我觉得本节内容对PSC的治疗上并没有太大的新意（毕竟文章重点也不在治疗上）。
To date, no medical therapy has proven to have a significant impact on clinical outcomes in PSC.[1] There are critical obstacles to the development of new therapies, such as a lack of statistical power and the slow and variable progression of the disease. Clinical trials are also hindered by the lack of disease activity markers associated with prognosis that can be used as endpoints. The window of treatment opportunity in PSC is unclear, and the point at which medical treatment may no longer be beneficial has not been identified.[127] ALP, along with fibrosis progression markers (histology, liver stiffness measurement, and serum fibrosis markers), is the current gold standard endpoint but is insufficientdue to a silent inflammatory process leading to disease progression that is difficult to detect.[128]
In addition, the patchy distribution of fibrosis makes histology and liver stiffness measurement variable and unreliable. Early-stage disease with low ALP levels where immune-focused therapies are most likely to play a role, progresses very slowly.[129,130] Consequently, drugs tested in short-term trials always risk being shown as ineffective, and patients with early-stage PSC with normal ALP levels are excluded from clinical trials. Conducting small, randomized studies over a short exposure time may result in potentially important drugs being dismissed despite their effectiveness.
The first randomized study in PSC was published in1988, using D-penicillamine which was known to be effective in rheumatoid arthritis.[131] Studies on corticosteroids followed, both orally and intrabiliary, and they showed no convincing beneficial effects but led to adverse metabolic and systemic effects.[132-137] Therefore, the use of steroids is not recommended in the recent clinical guidelines to treat PSC.[138,139] Very limited data exist on other immunosuppressive drugs. There are small, non-randomized, trials or pilot studies of azathioprine,[136]methotrexate,[140] cyclosporine,[141] tacrolimus,[142] mycophenolate mofetil,[143] and etanercept[144] usage. While tacrolimus, mycophenolate mofetil, and cyclosporine showed modest biochemical improvements, these drugs demonstrated no significant treatment benefits to justify their use, especially given their substantial adverse effect profiles.[141]
The most used drug today is UDCA.[139,145]UDCA improves ALP levels, but no clear survival benefit has been shown.[146] Its mechanisms of action on the immune system are somewhat unclear, but UDCA is known to exert a direct effect on adaptive immunity by inhibiting DCs.[147]
The development of new immune therapies or biologics in lBD is rapidly advancing. Targeting gut inflammation through drugs or colectomy or the gut microbiome itself is hypothesized to play an important role in PSC progression as well. Unfortunately, immunotherapies effective for lBD have not demonstrated clear efficacy for PSC. Neither anti-TNF therapies (infliximab and adalimumab)[148-150] nor vedolizumab (integrin α4β7 blockade)[151-153] have been associated with improvements in cholestatic markers despite their effectiveness in treating lBD.[154]
Results from a retrospective study on the effect of the JAK inhibitor tofacitinib showed some promising results with improvement of cholestasis in PSC-lBD.[155] There is one interesting ongoing phase Ⅱ trial using CM-101 that targets the soluble protein CCL24, promoting fibrotic and inflammatory activities in the liver through its receptor, CCR3(ClinicalTrials lD:NCT04595825). Finally, more experimental approaches, such as autologous hematopoietic stem cell transplantation[156] and autologous Treg transfer[157], have also been proposed.
Effective treatment is urgently needed for PSC. There are ongoing trials, including some experimental efforts. So far, immune-focused treatments, unfortunately have failed, but the rapidly growing field in lBD is also promising for PSC. However, further understanding of the immunopathology of PSC is required to choose the most promising immune treatment targets.
