診斷乾癬與接受治療嚴重傳染病的風險：系統性回顧

Abstract

背景： 乾癬是一種慢性的免疫相關皮膚疾病，有些病例還會合併有乾癬性關節炎。 相關研究指出：免疫抑制會增加感染的機率。另外，乾癬的病因既然是免疫失調，其本身的嚴重程度與針對免疫調節的乾癬治療方式（包括全身性抗乾癬治療與生物製劑）也可能會影響感染的種類與風險。此外，宿主的合併症，包括糖尿病、慢性阻塞性肺病、慢性腎病等，也可能會影響感染的風險，甚至嚴重感染到住院或死亡。因此，我們用流行病學的角度，針對被診斷患有乾癬以及所接受的乾癬相關治療做為暴露，以嚴重感染症的風險做為結果的人口群研究，從事系統性文獻回顧。 方法： 以乾癬、乾癬性關節炎、感染、嚴重感染、生物製劑與全身性抗乾癬治療等關鍵字，在 PubMed/MEDLINE 與 EMBASE 文獻資料庫中搜尋2010年至2022年期間發表在英文同儕審查期刊中之流行病學研究。並以流行病學方法的角度，摘取重要資訊、整理研究方法與各比較組定義之細節後，將優劣加以評析，歸納整理出流行病學相關實證之強弱，以做為未來相關人口群相關研究之基礎。 結果與討論： 從符合選擇標準的23個流行病學研究研析中，我們發現診斷患有乾癬、接受某些種類生物治療或全身性抗乾癬治療的人，可能具有較高的嚴重感染症風險，包含呼吸道、腸胃道和皮膚軟組織感染等。但針對罕見伺機感染（主要為結核病）為結果的研究中，在控制干擾因子之後，並沒有足夠證據指出風險會增加。這些不一致的研究結果，可能的原因包含：比較組的暴露（臨床診斷乾癬、乾癬嚴重程度與相關治療方式）定義不同、不適切的比較組、樣本數太小以及未充分控制干擾因素（包含皮膚微生物分布、乾癬相關基因和增加易感受的環境與生活型態）等。也因為這些流行病學研究的異質性過高，無法進行統合分析。為了進一步研究乾癬本身以及相關的治療是否會改變嚴重感染症的發生機率，我們建議研究者應針對分子生物學的致病機轉來建立新的研究假說，並針對這些假說，一一架構出合理的比較組別，以大規模長期追縱樣本，更重要的是收集個人層次的詳細乾癬治療過程資料，才能獲得最後的結論。相關研究成果，將可嘉惠乾癬病患，提供皮膚科醫師更多在乾癬的臨床治療上具有實證的資訊，幫助乾癬患者獲得最適切的治療以提升生活品質，同時降低不必要的感染風險，有效達成乾癬臨床管理目標。 結論： 有關乾癬本身的致病機轉或其各種治療方式（尤其是會影響免疫系統運作方式的生物製劑）是否會升高嚴重感染症風險這個研究命題，在流行病學上還尚未有定論。但若能改善流行病學研究方法，產生出更好的流行病學證據，將可提供有用資訊給臨床工作者考量最佳治療方式，一方面有效控制乾癬，但卻不至於增加感染症風險。

Background: Psoriasis is a chronic immune-mediated skin disease which may involve joints, presenting psoriatic arthritis. Related research evidence demonstrated that immune suppression might lead to infection. Since psoriasis has been well-characterized as a disease caused by immune dysregulation, its development and severity were thus suggested to impose various infections on people with psoriasis. Furthermore, comorbidities of the host, including diabetes mellitus, chronic obstructive pulmonary disease, and chronic kidney diseases, may also influence their risks of infection, even resulting in hospitalization or death. Furthermore, treatment of immunomodulated therapies against psoriasis may play a critical role, for which systemic antipsoriatic treatments and combined biological therapy are applied to moderate to severe psoriasis cases in routine practice. To re-organize the literature about psoriasis and / or its treatments as exposure and serious infection as the outcome, we attempted to conduct a systematic review with the consideration of epidemiologic methods. Methods: We searched the PubMed/MEDLINE and EMBASE databases for epidemiologic articles published in peer-reviewed English journals from 2010 to 2022 with the keywords of 'psoriasis', 'psoriatic arthritis', 'infection', 'serious infectious disease', 'biologically targeted therapy', and 'systemic antipsoriatic therapy. With the perspectives of epidemiologic methods, we extracted key information on research methods and detailed comparison scenarios, followed by systematical evaluations on the advantages and disadvantages of qualified studies focusing on the level of evidence as the basis of future population-based research in related fields. Results and discussion: Reviewing 23 qualified epidemiologic studies, we found that people with psoriasis (including psoriatic arthritis) treated by specific biologics or systemic antipsoriatic therapies were at an increased risk of serious infectious illness, including respiratory, gastrointestinal, skin, and soft tissue infections. However, studies about rare opportunistic infections (mainly referring to tuberculosis) did not reveal sufficient evidence of increased risks after controlling confounders. Potential reasons of these inconsistent outcomes contained various definitions of the exposures (clinical diagnosis of psoriasis, severity of psoriasis, and related treatments), inappropriate comparison scenarios, limited sample sizes, and the existence of residual confounders (i.e., psoriasis microbial profiles, psoriasis-related genes, environment-related and lifestyle factors for increased susceptibility). Because of the heterogeneity of these studies in variant control comparison of therapies, definition of paticipants to outcomes, and adjustments of confounders, it was too challenging to perform advanced meta-analyses. To further investigate the topic about if psoriasis itself and its related treatments would elevate the risks of serious infections, we recommend researchers to generate new hypotheses based on a profound understanding of the pathogenesis of psoriasis for its molecular biology, to construct reasonable comparison scenarios of exposure groups in response to the hypotheses, to perform long-term follow-up of studies with huge sample sizes, and, most importantly, to collect data on the detailed treatment processes at individual levels for making the final conclusions. In the future, related research outcomes will benefit people with psoriasis by providing more evidence-based information for the clinical practice of dermatologists to offer better treatments for people with psoriasis and improve their quality of life without concerns about the unnecessary risks of infections. Conclusion: Whether psoriasis for its pathogenesis or related treatments, especially the biologics that might interfere with people's immune regulation, could increase the risk of serious infections is still far from conclusive in epidemiology. More substantial evidence generated by the improvement of epidemiologic methodology will provide adequate information to clinicians for better management of psoriasis but no unwanted increase of infection risks.