Efficacy and safety of adalimumab in comparison to infliximab for Crohn's disease: A systematic review and meta-analysis

lNTRODUCTlON

Our current study has some limitations. First, we only included observational studies and failed to control adequately confounders, such as disease severity, disease phenotype, steroid use,

. In addition to clinical benefits, we should consider other factors, such as patients’ preferences and costs. Future studies are needed to address these questions.

IFX, a chimeric monoclonal antibody against TNF-α, is the first approved anti-TNF-α for moderate to severe CD. ADA is a humanized monoclonal antibody against TNF-α. IFX is given by intravenous infusion every 8 wk, whereas ADA is administered subcutaneously every 4 wk. Differences in immunogenicity and route of administration among them allow for potential variability in therapeutic properties and efficacy. However, clear recommendations have been limited due to a lack of head-tohead treatment comparison. A network meta-analysis published in 2014 found that ADA may be the most efficacious agent for maintenance of remission in CD in biologic-na?ve patients[3], while many new clinical practice experience studies have shown their effectiveness and safety data were comparable. Furthermore, even though there has been cumulative research, few studies have focused on secondary loss of response, anti-TNF na?ve or non-na?ve patients, and the benefits of treatment optimization, such as dose intensification, shortening interval, and combination with immunomodulators. We performed a meta-analysis to synthesize these results and compared the efficacy and safety of ADA and IFX.

MATERlALS AND METHODS

Our protocol was registered with PROSPERO (CRD: 42021191655). We followed the Preferred Reporting Items for the Systemic Review and Meta-Analysis guidelines.

Search retrieval

We performed literature search of electronic sources, including PubMed, Cochrane Library, Web of Science, and Embase, from initiation until October 31, 2020. No language restrictions were applied. The search terms included “Crohn disease,” “adalimumab”, and “infliximab” as Medical Subject Headings terms and their entry terms (Crohn disease: Crohn*; ileitis. Adalimumab: Humira; Exemptia. Infliximab:Remicade) to improve search outcomes. We also screened references of relevant articles to avoid omissions.

Inclusion and exclusion criteria

We included cohort studies comparing ADA and IFX for treating adults with CD. Comparisons of induction of remission and response rates, maintenance of remission and response rates, secondary loss of response rates, and the incidence of adverse events were among the outcomes of included studies.Excluded studies included those conducted in the pediatric population, those that did not investigate patients with inflammatory bowel disease, and those that did not report any outcomes of interest.

Study selection

Six studies with 1307 patients were included (603 receiving ADA and 704 IFX therapy)[5-7,9,12,17]. There was no statistical difference between the two treatments (OR: 1.01,95%CI: 0.65-1.55,

= 0.97). Heterogeneity was notable (

= 0.05,

= 54%) (Figure 4). Heterogeneity was linked to the study by Narula

[9], which found that IFX had more rate of loss of response than ADA.On sensitivity analyses, the results remained the same after excluding any one study(Supplementary Table 1). There was also no significant difference between ADA and IFX when subgroup analysis was done (Table 2).

Data extraction

Five studies (1040 patients) recorded induction of response[6,7,9,10,15]. No difference was shown between groups in response rates (OR: 1.27, 95%CI: 0.93-1.74,

= 0.14). Of the 1040 patients in five studies, 515 received ADA therapy. The heterogeneity of those studies was insignificant (

= 0.58,

= 0%) (Figure 2A). Sensitivity analysis showed no significant changes to the exclusion of any one of the studies (Supplementary Table 1). Subgroup analysis revealed no remarkable difference between groups (Table 2).

在折頁機構(gòu)中引入彈簧后，折頁機構(gòu)的增加了8個局部自由度，4個為軸承的徑向動態(tài)剛度引起的變形量lki，表現(xiàn)為彈簧受到壓縮變形；4個為軸承徑向壓縮的角度γi，表現(xiàn)為彈簧壓縮方向的變化.將運動副間隙假設(shè)成無質(zhì)量剛性桿，將軸承滾子假設(shè)為彈簧.用剛性桿與彈簧組合模擬折頁機構(gòu)各運動副接觸情況，即為剛性桿彈簧組合假設(shè).

The outcomes of interest included: (1) Induction of clinical remission defined as Crohn’s disease activity index (CDAI) ＜ 150, Harvey Bradshaw Index (HBI) ≤ 4, or by physician's global assessment after≤ 14 wk; (2) Induction of clinical response was defined as ΔCDAI ≥ 70, ΔHBI ≥ 2, or by physician's global assessment after ≤ 14 wk; (3) Maintenance of remission referred to clinical remission after ≤ 54 wk; (4) Maintenance of response referred to clinical response after ≤ 54 wk; (5) Secondary loss of response was defined as a reappearance of disease activity after achieving induction response, coupled with the need to change treatment, including dose intensification, the addition of an immunomodulator,or need to discontinue treatment; and (6) Secondary outcomes included a comparison of the incidence of overall adverse events, severe adverse events, and opportunistic infections in trials of maintenance therapy.

“哼哼嘰嘰”、“唱唱咧咧”這兩個詞中的“哼”和“唱”是可以單獨成詞的，而“嘰”和“咧”不可以。重疊后也是一樣，AA式“哼哼”和“唱唱”是可以獨立使用的，而BB式“嘰嘰”和“咧咧”一般不能單獨使用。但“嘰嘰”作為疊音詞時改變聲調(diào)，音為“jìji”時變成動詞是可以單獨成詞的，當然，這種情況是比較少見的。

綜上所述，在臨床護理教學(xué)中采用CPBL教學(xué)模式，力求提高臨床護理教學(xué)質(zhì)量，為CPBL教學(xué)法在臨床護理學(xué)中廣泛應(yīng)用提供參考。

Quality assessment

One author assessed the quality of included studies through the Newcastle-Ottawa Quality Assessment Scale (NOS). High-quality studies were defined by a total score of ≥ 6.

Statistical analysis

RevMan 5.3 and Stata 16.0 software were used for statistical analysis. Odds ratio (OR) and concomitant 95% confidence interval (CI) were evaluated for the quantitative analyses. The random-effect model was used. Heterogeneity was explored by calculating

and employing the Q test. An

estimate ＞ 50% and a

＜ 0.05 were regarded markers of significant heterogeneity, and its causes were investigated. We performed sensitivity analyses and subgroup analyses to detect the source of heterogeneity.

＜ 0.05 was considered to indicate a significant difference. Subgroup analyses were conducted based on the following grouping criteria: (1) Studies evaluating outcomes on anti-TNF na?ve patients

studies on non-na?ve patients; (2) Studies evaluating outcomes on more perianal diseases in IFX group

equal perianal disease in IFX and ADA group; (3) Studies evaluating primary outcomes given with treatment optimization,

shortening the administration intervals, increasing the dose, and/or combination with immunomodulator therapy; and (4) Studies evaluating secondary outcomes at ≤ 48 wk

＞ 48 wk.Funnel plots and Egger’s test was used to test for publication bias.

開展探究式實驗的性別、年級和GPA并不影響學(xué)生對Q2和Q3的回答,但是女生比男生更相信探究式實驗有助于強化她們對環(huán)境基本概念和應(yīng)用的理解。對于Q4,三學(xué)年132位所調(diào)查的學(xué)生中,壓倒性的92.4%學(xué)生是第一次接觸探究式實驗。僅有20個學(xué)生(占7.6%)以前接觸過類似的探究式實驗,這些不足8%的學(xué)生可能是由于外部課程(基礎(chǔ)學(xué)科實驗室或高中[12])而接觸探究式實驗。

RESULTS

Literature search

A preliminary search of the above database identified 2228 documents. Of these, we removed 562 duplicates, discarded 1632 studies after screening the titles and abstracts, and assessed the full text of 34 studies for eligibility. Finally, 14 cohort studies were included, and 20 were excluded. The flow diagram describes this process in detail (Figure 1).

Study characteristics

Study design, outcomes, the definition of outcomes, inclusion criteria, and follow-up time differed among the included studies. Our meta-analysis consisted of two prospective cohort studies and 12 retrospective cohort studies. Three pieces of research evaluated maintenance response or remission at 54 wk[4-6], five at 48 wk[7-11], and one at 26 wk[12]. Regarding the definition of outcomes, most incorporated studies evaluated clinical response or remission by CDAI or HBI except for the study by Macaluso

[10]. In addition, seven studies only included anti-TNF-na?ve patients[4,7-9,12,13], and no study only included patients who failed anti-TNF treatment. Follow-up intervals across studies varied,ranging from 4 to 14 wk for induction period and 26 to 168 wk for maintenance period. The high NOS scores reflected the high quality of the enrolled studies. Thirteen studies got a score of ≥ 6, except for the study by Bau

[14], which scored 5. Table 1 showed the overall characteristics of the selected studies.

1.1 對象 將上海市按地域劃分為9大區(qū)域，于2010年8月—2011年6月抽取每個區(qū)域1所社區(qū)醫(yī)院，每所社區(qū)醫(yī)院抽出1名社區(qū)護士，其中符合條件的為16名，隨機分為實驗組和對照組各8名，均為女性;年齡28～48歲;從事護理工作時間為4～28年;均未接觸過相關(guān)培訓(xùn)。

Primary outcomes

We collected the following variables: First author’s name, year of publication, country or area, study design, number of patients, gender, median age, Montreal classification, duration of follow-up, previous treatment, and outcomes of interest. The endpoint of this meta-analysis mainly included the induction response and remission, maintenance response and remission, overall adverse events rate, severe adverse events rate, and the rate of opportunistic infections.

When combining all four studies[6,8,9,16] reporting induction of remission data(318 on ADA therapy and 494 on IFX therapy), we found no difference between the two groups of patients (OR: 1.11, 95%CI: 0.78-1.57,

= 0.57). Heterogeneity was low (

= 0.85,

= 0%) (Figure 2B).Subsequent subgroup analysis showed similar results (Table 2). In sensitivity analyses, excluding any one of the studies did not significantly impact the results (Supplementary Table 1).

Of the 14 studies, seven reported the response rate in maintenance therapy[4,6,7,9-12]. A number of 1828 patients were included: 896 IFX-treated

932 ADA-treated. Data analysis showed that ADA and IFX had a similar rate of maintenance of response (OR: 1.08, 95%CI: 0.76-1.53,

= 0.67). Heterogeneity was significant (

= 0.03,

= 56%) (Figure 3A). Cosnes

[12] evaluating response at 26 wk increased heterogeneity. In the sensitivity analysis, the result remained unchanged with the exclusion of any study (Supplementary Table 1). Subgroup analyses also showed no difference between the two groups (Table 2).

There were 770 patients (328 on ADA therapy) available for analysis from six studies[5-9,11]. Data analysis showed that ADA and IFX had a similar rate of maintenance of remission (OR: 1.26, 95%CI: 0.87-1.82,

= 0.22). Heterogeneity was low (

= 0.29,

= 19%) (Figure 3B).Subgroup analyses also showed no statistical differences (Table 2). Sensitivity analysis indicated that the results were stable (Supplementary Table 1).

Two investigators (Yang HH and Huang Y) independently screened the titles, abstracts, and full texts of all papers to determine trial eligibility for inclusion. Investigators used a consensual approach to determine the inclusion or exclusion of selected studies after full-text assessment. Any disagreement was resolved through discussion or with a third researcher. The study characteristics were extracted independently by two authors using a standardized datasheet.

Secondary outcomes

The incidence of overall adverse events was recorded in a total of eight cohort studies[4,5,7-11,14] that included 1653 patients, of which ADA was less than IFX (OR: 0.62, 95%CI:0.42-0.91,

= 0.02). There was high heterogeneity (

= 0.04,

= 53%) (Figure 5A). Subgroup analysis revealed that ADA had fewer overall adverse events than IFX in ≤ 48 wk follow-up time (OR: 0.50,95%CI: 0.33-0.76,

= 0.001); and in anti-TNF-α-na?ve patients, IFX had more adverse events (OR: 0.67,95%CI: 0.50-0.89,

= 0.005) (Table 2). Sensitivity analysis indicated that the results were slightly unstable (Supplementary Table 1).

Our analysis of seven studies[6,8,9,11,12,14,15] with a total of 1547 patients showed ADA had a similar rate of severe adverse events with IFX (OR: 0.75, 95%CI: 0.32-1.72,

= 0.49).Sensitivity analysis was performed due to notable heterogeneity (

= 0.003,

= 72%) (Figure 5B).Heterogeneity mainly originated from Zorzi

[6] with more severe adverse events occurring in IFX therapy. The result remained unchanged with the exclusion of any study (Supplementary Table 1).Subgroup analysis also showed similar results (Table 2).

Six studies[4,7,9,13-15] reported side effects, with a total number of 1910 cases(ADA: IFX = 922:988). Opportunistic infections rates in the IFX and ADA groups were similar (OR: 0.96,95%CI: 0.66-1.40,

= 0.83), and no apparent heterogeneity was detected (Figure 5C). There was no significant difference when subgroup analysis was done (Table 2). Sensitivity analysis showed no significant changes when any one of the studies was excluded (Supplementary Table 1).

Publication bias and GRADE evaluation

The symmetry of the funnel plot indicated there was no publication bias (Figure 6). The Egger’s test showed no significant publication bias for maintenance of response (

= 0.7024 ＞ 0.05), maintenance of remission (

= 0.1003 ＞ 0.05), secondary loss of response (

= 0.0510 ＞ 0.05), and overall adverse events (

= 0.6717 ＞ 0.05). GRADE evidence of all outcomes was judged as “l(fā)ow”. The results are shown inTable 3.

DlSCUSSlON

The immunogenicity of anti-TNF-α agents triggered the formation of anti-drug antibodies (ADAbs)specific to the agent administered. ADAbs of IFX or ADA and reduced serum concentrations in association with ADAbs together lead to decreased clinical benefit and increased adverse events.Although the immunogenicity of IFX is usually higher than that for ADA, we found both of them have similar response characteristics in CD patients. In our meta-analyses, no significant differences in primary outcomes were found between groups treated with IFX and ADA. These results were consistent with the results of most published studies[5-12,15-17]. One unexpected finding was the extent to which the overall adverse events rate of IFX was higher than that of ADA. Our meta-analysis indicated that physicians may choose on an individual basis, according to a possible history of adverse events to either IFX or ADA and to patient compliance, to give either an intravenous infusion or a selfadministered subcutaneous injection.

CD is a heterogeneous disease, and the therapeutic efficacy differs between the types of disease,

,location of disease, the existence of stenosis and/or fistula, or perianal involvement. There was no significant difference between IFX and ADA groups in the location of disease and existence of stenosis and/or fistula of included studies. However, IFX patients had more perianal diseases in the studies of Benmassaoud

[7], Varma

[8], Narula

[9], and Cosnes

[12]. Clinicians tended to choose IFX over ADA in patients with more severe disease activity or phenotypes (perianal disease) due to its intravenous administration and weight-based dosing schedule. We attempted to adjust for these differences through subgroup analysis, which led to the same conclusions (Supplementary Tables 2 and 3). Additionally, Ji

[18] found the cumulative rate of nonrecurrence or aggravation of fistula at 24 mo was not significantly different between IFX and ADA groups (62.5%

83.9%,

= 0.09).Current evidence suggested that IFX and ADA had similar effects in patients with perianal disease.

2.2 對選用的復(fù)合（混）肥或作物專用肥，不含有機質(zhì)或含量在15%以下的肥料，要增加充分腐熟的畜禽純干糞不少于20公斤/畝，可有效的杜絕或緩解玉米苗期肥害。

（4）位置。肺癌腫塊分布可分為左肺葉、右肺葉、上葉、下葉幾個部分。在36例周圍型小肺癌患者中，腫塊在左肺的上葉有8例，其比例為22.22%；中葉的有4例，其比例為11.11%；下葉的有8例，其比例為22.22%?；颊咧?，腫塊在右肺的上葉有4例，其比例為11.11%；在中葉的有2例，其比例為5.56%；在下葉的有10例，其比例為27.78%。

Co-immunosuppression affected the results of the analysis. The finding that combination therapy with an immunomodulator is superior with IFX but not with ADA was reported in Kestens

[4],Benmassaoud

[7], and Doecke

[16]. The possible reason is that IFX combined with immunomodulator treatment reduces its immunogenicity. However, clinical efficacy of ADA combination therapy did not differ from that of ADA monotherapy (71.8%

68.1% at week 26,

= 0.63)[21]. Therefore, more patients in the IFX group were combined with immunomodulator treatment than in the ADA group in the Narula

[9] study. No change was found in results after sensitivity analysis was conducted.Patients were on concomitant immunomodulation at anti-TNF induction to improve the efficacy of the induction of the remission and discontinued co-therapy due to adverse effects or intolerability (from the beginning). When loss of response occurred, concomitant therapy was resumed (later add on). Only the Cosnes

[12] study used immunomodulators later. No different results were found after sensitivity analysis was performed. Furthermore, CD patients who lost response were allowed to shorten intervals and double dosage. These optimization strategies also impacted the results. We conducted subgroup analyses comparing the outcomes between using dose optimization and not and found the clinical effect of ADA was similar to IFX.

Similar to the findings of many studies[4,10,17], the significantly higher rate of overall adverse events can be seen in patients using IFX, which could be attributed to infusion or allergic reactions.Benmassaoud

[7] reported that IFX group patients were more likely to have infusion or injection reactions than ADA. A higher rate of allergic reactions in the IFX was observed in a study by Narula

[9]. However, we noted that the difference did not exist in anti-TNF-α non-na?ve patients and with long follow-up time. We were unable to evaluate long-term safety due to the different follow-up times of each study. Larger and long-term comparison studies will be necessary. In addition, the instability of the results also require further studies to establish these findings.

Biologic-na?ve or non-na?ve patients were important factors to influence the results. It is controversial whether ADA had similar efficacy to IFX in previous anti-TNF exposure CD patients. Macaluso

[10]compared clinical benefits between IFX and ADA only in biologic non-na?ve CD patients and reported that there was no difference in clinical benefits at 12 wk and after 1 year (

= 0.600 and

= 0.620,respectively). A retrospective case-control study[19] found that the risk for ADAbs to IFX was higher than ADAbs to ADA when patients had prior antibodies to anti-TNF. They did not investigate clinical efficacy. However, Sasson and Ananthakrishnan[20] found that patients with high ADAbs titers exhibited similar rates of clinical efficacy to ADA therapy compared to those with low titers (at 3 mo and 12 mo

= 0.81 and 0.62 respectively). This may mean IFX and ADA have similar efficacy in previous anti-TNF exposed CD patients. Our findings indicated that either in na?ve or non-na?ve patients ADA and IFX had similar clinical response and remission. More studies conducted on previous anti-TNF exposure CD patients will be necessary.

Additionally, we failed to evaluate long-term results due to the different follow-up times of each study. Inokuchi

[22] performed a retrospective study to evaluate long-term prognosis. They observed that the rates of cumulative steroid-free remission rates and surgery-free did not differ significantly between the two groups after a median observation period of 64.2 mo (

= 0.42 and

=0.74, respectively). The goal of CD treatment requires more than clinical healing. Mucosal healing and tissue healing are expected to stop disease progression and reduce recurrence. Tursi

[15] found that mucosal healing and histological healing were comparable between the two groups (

= 0.946 and

=0.895, respectively).

羅璨璨(1994—)，女，福建仙游人，碩士研究生，研究方向為巖土工程數(shù)值模擬、大壩與基礎(chǔ)工程等方面的研究工作。

通過BIM技術(shù)完成的建筑模型是建筑的真實反映，可以對建筑施工進行總體計劃，提高工作效率，保證工程進度，使高水平的施工技術(shù)運用到復(fù)雜的項目中，同時增強設(shè)計與施工之間的聯(lián)系。

Although biologic agents targeting TNF-α have achieved remarkable progress in treating CD, some patients do not respond to the induction therapy or lose response over time (secondary loss of response). The anti-drug antibodies or low serum drug concentrations play a critical part in the loss of response[23]. If ADA is superior to IFX for remission, ADA should have a lower rate of secondary loss of response than IFX. However, we failed to find a difference in the secondary loss of response between the two groups, which contradicted our hypothesis. It was further demonstrated that both have similar effects.

This work is the first direct comparison meta-analysis to evaluate the comparative effectiveness and safety of ADA and IFX in CD. Previous network meta-analyses addressed similar outcomes in the Bayesian setting indirect comparison. In our study, we enrolled comparative trial data resulting in more credible results. Furthermore, head-to-head clinical trials comparing ADA and IFX would not be feasible in the future; therefore, our studies will help guide optimal therapies.

是啊，渺小感！想必很多登山的人都有過這種渺小感，登上高峰，覺得天空蒼茫浩渺，大地寬廣博大，人在天地之間，感覺自己慢慢縮小，小成一只蟻，小成一根草。人生渺茫，世事滄桑，諸多感受一擁而上，忽然間人的眼神里就流露出崇敬之光——相比大自然，人算得了什么，又有什么理由狂妄自大呢？

Crohn's disease (CD) is an incurable chronic progressive condition characterized by abdominal pain,diarrhea, and weight loss. Aminosalicylic acid preparations, glucocorticoids, immunosuppressants, and biological agents have been used for treatment. Of these, biological agents are most widely used,especially anti-tumor necrosis factor-α (anti-TNF-α) blockers, including infliximab (IFX) and adalimumab (ADA). They all have been proven effective in inducing and maintaining remission and are routinely used in the treatment of CD[1,2]. We do not know, however, which treatment should be considered the priority?

CONCLUSlON

IFX and ADA have similar response characteristics either in anti-TNF na?ve and non-na?ve CD patients,and ADA therapy has fewer overall adverse events. Our study indicates that IFX or ADA can be freely chosen as treatment based on physician and patient agreement. Eventually, the decision of which treatment to start may depend on factors such as patient preference and cost.

ARTlCLE HlGHLlGHTS

ACKNOWLEDGEMENTS

We would like to thank all authors of the included primary studies.

眾所周知，授人以魚不如授人以漁，課堂教學(xué)更是如此。作為教師的我們不可能手把手地教學(xué)生讀每一本課外書，因而閱讀方法的指導(dǎo)就顯得尤為重要。在閱讀指導(dǎo)課上，我首先就對學(xué)生進行了閱讀整本書的方法指導(dǎo)。

FOOTNOTES

Yang HH and Zhou XC contributed to study design; Yang HH, Huang Y, and Wang RN contributed to the literature search; Yang HH, Huang Y, and Zhou XC participated in data extraction and analysis;Yang HH and Huang Y wrote the paper.

Nothing to disclosed.

The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.

在手術(shù)醫(yī)師授權(quán)方面，實現(xiàn)了對所有臨床手術(shù)病種及所有外科醫(yī)生（含介入醫(yī)生）的再授權(quán)，并根據(jù)醫(yī)務(wù)人員職稱、工作能力授予相應(yīng)手術(shù)等級資質(zhì)，規(guī)范了手術(shù)操作授權(quán)，實行了手術(shù)分級動態(tài)管理。多年來，醫(yī)院手術(shù)并發(fā)癥發(fā)生率一直低于國家的基準值1.01%。

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Hua-Hua Yang 0000-0002-0065-2741; Yi Huang 0000-0001-8049-1900; Xu-Chun Zhou 0000-0002-5128-3149; Ruo-Nan Wang 0000-0003-2049-6827.

Fan JR

Filipodia

Fan JR

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