Biologics for the treatment of inflammatory bowel disease in adults: rational selection and conversion

summary

A variety of biologics have been approved for the treatment of inflammatory bowel disease (IBD).

However, due to the lack of head-to-head randomized controlled studies comparing efficacy and safety between biologics, and the lack of methods to accurately predict the efficacy of biologics, clinicians are often confused
about how to select biologics.
This article refers to the existing clinical research evidence, combined with international mainstream opinions and China's application experience, and puts forward suggestions on the selection and conversion of biologics in the treatment of IBD for peer reference
.

More than 20 years ago, the first biologics anti-tumor necrosis factor (TNF)-α monoclonal antibody (hereinafter referred to as monoclonal antibody), namely infliximab (IFX), was approved for the treatment of Crohn′s disease (CD), opening a new era of biologic therapy for inflammatory bowel disease (IBD).
Since then, new anti-TNF⁃α monoclonal antibodies, biologics with different targets, and low-molecular weight drugs have been approved for the treatment
of CD and/or ulcerative colitis (UC).
The results of phase III clinical trials of these approved drugs are shown in Tables 1 and 2
.
At present, China has approved IFX, adalimumab (ADA) and vedolizumab (VDZ) for the treatment of CD and UC, ustekinumab (UST) for the treatment of CD and UC, ustekinumab (UST) for the treatment of CD, and this journal published expert recommendations on standardizing the use of these biologics in 2021 [1].

There is currently no consensus to guide the rational selection of biologics for IBD, mainly due to the lack of head-to-head randomized controlled trials (RCTs) comparing the efficacy and safety of biologics, and even more so on the predictors of the efficacy of biologics
.
This article refers to the existing clinical research evidence, analyzes and compares the efficacy and safety of these drugs, and then combines the international mainstream opinions and China's application experience to put forward suggestions on the selection and conversion of biologics in the treatment of IBD for clinical reference
.
1.
Indications for the use of biological agents

(1) CD

Biologics are indicated in patients with moderate to severe CD who do not respond well to and/or cannot tolerate traditional therapies such as glucocorticoids and/or immunosuppressants[1].

Harvey⁃Bradshaw is generally defined as moderate to severe CDAI based on the Crohn′s disease activity index (CDAI) ≥ 8 or Best CDAI ≥ 220 [2].

However, CDAI mainly reflects the degree of disease activity of CD in a certain period of time, and cannot truly and comprehensively reflect the severity
of the disease.
Therefore, the International Organization for IBD Research (IOIBD) has proposed an IBD overall disease severity index, which is closely related to the long-term prognosis of the disease (disease-related complications, surgical resection, impact on quality of life) [3].

。 According to the degree of structural damage to the gut, inflammatory burden and impact on quality of life, the risk factors for poor prognosis in the IBD overall severity index are as follows (in order of highest to lowest): deep or large ulceration of the intestinal mucosa as seen endoscopy or imaging, concomitant fistula and/or perianal abscess at diagnosis and treatment, history of bowel resection (especially small bowel resection > 40 cm), presence of an enterostomy, extensive bowel lesions (ileal involvement > 40 cm or whole colon), rotten stool at least 10 times per week, intestinal stricture at diagnosis and treatment, C⁃ Significantly elevated C⁃reactive protein (CRP), poor symptom improvement by biologics and/or immunosuppressants, hypoproteinemia, anorectal-related symptoms, anemia, daily abdominal pain, glucocorticoid therapy
in the past 1 year.
Those with the above high-risk factors can be considered as high-risk patients
for CD.
For patients at high risk of CD, especially those with a high overall disease severity index, early treatment with biologics is appropriate [4⁃5].

A recent meta-analysis of 6168 patients with CD in 25 RCTs showed that the induction rate of biologic agents in patients with CD with a short course (≤ 18 months) was significantly higher than that in patients with a long course of disease, suggesting that early biologic therapy for CD may be more effective [6].

For patients with mild to moderate CD, conventional therapy [glucocorticoids and/or immunosuppressants] is recommended, and biologic therapy may be considered if treatment fails or recurs frequently and there is objective evidence of inflammatory activity [4].

(ii) UC

Biologics are indicated in patients with moderate to severe UC who do not respond well to and/or are intolerant to conventional treatments [glucocorticoids and/or immunosuppressants] [1].

Generally, the total score of the modified Mayo score of ≥ 6 and the endoscopic score of ≥ 2 are defined as moderate to severe UC.

According to Truelove and Witts criteria, acute severe lcerative colitis (ASUC) refers to the ≥ of bloody stools 6 times/day in hospitalized UC patients, accompanied by at least one systemic toxicity [heart rate >90 beats/min, body temperature > 37.
8°C, hemoglobin < 105 g/L, erythrocyte sedimentation rate (ESR) >30 mm/1 h］［2］
。

Early use of biologic agents may be considered in high-risk UC patients who may require colectomy [7].

Risk factors include generalized colitis, deep ulceration of the intestinal mucosa, age≤ 40 years, markedly elevated inflammatory markers (CRP and ESR), and the need for glucocorticoid therapy
at onset.
The guidelines of the American Gastroenterological ssociation (AGA) endorse this view [8], but the European Crohn's Disease and Colitis Organization (ECCO) guidelines mention but are not explicitly recommended [9], and how to grasp them in clinical practice needs to be further explored
.
When ASUC patients are ineffective after 3 ~ 5 days of intravenous glucocorticoids, they should switch to therapy
.
IFX and cyclosporine are similarly effective as conversion therapy [7⁃8].

Second, the efficacy of various biological agents is compared

(<>) CD

1.
Induction and maintenance of clinical remission of intestinal CD: At present, there are no head-to-head RCT results comparing the efficacy of various biologics, mainly with the help of network meta-analysis of the results of placebo-controlled RCTs, the efficacy comparison between biologics is carried out, and the development and evaluation (grading of recommendations assessment, development and evaluation, The GRADE framework assessed the quality of the evidence [10].

The analysis of the efficacy of various biological agents by AGA is representative [10].

In terms of first-line biologics (no previous biologics) induced clinical remission of intestinal CD, analysis of results from eight RCTs in 1458 patients with CD found that IFX may be superior to UST (OR = 2.
14, 95% CI: 0.
89 ~ 5.
15) and VDZ (OR = 2.
20, 95% CI: 0.
79 ~ 6.
07) (low-certainty evidence), and it is uncertain whether ADA is superior to UST and VDZ, There was no statistically significant
difference in efficacy between UST and VDZ.
In terms of second-line biologics (previously used anti-TNF agents) to induce clinical remission of enteric CD, analysing the results of 6 RCTs in 1606 patients with CD found that ADA, UST, and VDZ were all more effective than placebo (moderate, moderate, and low evidence, respectively), and that ADA and UST may be more effective than VDZ, but the difference in efficacy between the three biologics is uncertain
due to very low-quality evidence 。 ADA may be better than UST (OR = 2.
19, 95% CI: 1.
15 ~ 4.
16) and VDZ (OR = 1.
96, 95% CI: 0.
93 ~ 3.
85) (low-certainty evidence) in maintaining clinical remission with biologics, with uncertain
differences in efficacy between other biologics.

Other studies on the efficacy of biologics for the treatment of CD require our attention
.
The results of an unpublished head-to-head randomized double-blind, double-simulated controlled study comparing UST and ADA as first-line biologics for moderate to severe CD (SEASVUE study) showed that the 8-week induced clinical response rate of the two biologics was similar (50.
3% vs.
47.
7%), and there was no significant difference in 52-week clinical response rate and hormone-free clinical response rate (65.
9% vs.
61.
0%, P = 0.
417; 60.
7% versus 57.
4%, P = 0.
485）
。 This study will provide the first high-quality evidence
that UST has the same efficacy as ADA as a first-line biologic.
Another study compared IFX and UST as first-line biologics for the treatment of CD, and post-hoc analysis of two RCT studies (420 patients) showed no significant difference in the 6-week clinical response rate (44.
9% versus 37.
9%, adjusted OR = 1.
22, 95% CI: 0.
79 ~ 1.
89) and clinical response rate (58.
4% versus 54.
9%, adjusted OR = 1.
25, 95%CI: 0.
82 ~ 1.
90) between the two biologics.
The results suggest that IFX and UST have similar rates of action as first-line biologic therapies [11].

Regarding the efficacy of VDZ and anti-TNF agents as first-line biologic agents for the treatment of CD, a retrospective study (EVOLVE study) collected continuous CD cases in the United States, Canada and Greece from September 2017 to December 2018, of which 215 patients were treated with VDZ and 266 were treated with anti-TNF agents, and the results showed no statistically significant difference in clinical response rates between the two biologic agents at 24 weeks (76.
6% vs.
68.
5%, P = 0.
10）［12］
。

In addition, there are many large-scale observational studies in the real world that have compared the efficacy
of UST with VDZ as a second-line biologic agent for the treatment of CD that is ineffective with anti-TNF agents 。 In a retrospective study of 239 CD patients who did not respond to anti-TNF preparations, the clinical response rate of 48 weeks of UST treatment was significantly higher than that of VDZ (54.
4% vs.
38.
3%, OR =1.
92, 95% CI: 1.
09 ~ 3.
39)[13]; Another prospective enrollment study of 203 patients with CD who did not respond to anti-TNF preparations suggested that 52 weeks of UST treatment had hormone-free clinical remission and a significantly higher rate of inflammatory index remission than VDZ (23% versus 10%, OR = 2.
74, 95% CI: 1.
23 ~ 6.
09) [14]
.
Studies of the VDZ efficacy prediction model suggest that VDZ has a poor efficacy in patients with CD with complications who have previously used anti-TNF preparations [15].

In general, based on current clinical evidence, IFX and ADA are options when selecting first-line biologics, with preliminary evidence suggesting that UST can be used as a side-by-side option and VDZ as a first-line biologic for CD treatment
of low quality.
For patients with primary failure of anti-TNF preparations, UST treatment is preferred; For secondary failure, ADA (preferably IFX trough concentration and antibodies) or UST therapy
is recommended.
VDZ can be used for moderate CD with primary or secondary failure of anti-TNF formulations without complications [5].

In general, remission-inducing drugs are used to maintain CD remission
.

2.
Treatment of other clinical conditions:

(1) Fistula CD: At present, there are only RCT studies of IFX for the treatment of CD fistula, and the results show that the rate of IFX induction and maintenance of fistula healing is significantly higher than that of placebo [16⁃17].

RCTs of other biologics for the treatment of CD fistula are mainly derived from post-hoc subgroup analyses
of RCT studies of biologics for the treatment of CD.
UST induced and maintained fistula healing rates were higher than placebo, and ADA or VDZ maintained fistula healing rates were higher than placebo, but the certainty of evidence was lower [10].

The vast majority of CD fistula in the above studies were fistulas
.

A retrospective multicenter study in France (the BioLAP study) suggested that UST had some efficacy in fistula [18].

99% of the patients in the study had previously received anti-TNF
preparations.
The healing rate of fistula at 6 months after UST treatment was 38.
5% (57/148) for patients with active fistula, and the recurrence rate of fistula in patients with inactive fistula was 22.
0% (13/59)
during the average follow-up period of 48 weeks after treatment.
At the same time, the BioLAP study also summarized the efficacy of VDZ in the treatment of fistula, showing that VDZ has limited value in the treatment of fistula [19].

During the average follow-up period of 33 weeks, 68% of patients stopped the drug due to no improvement of fistula or intestinal symptoms and adverse reactions, the healing rate of fistula in patients with active fistula was 22.
5% (23/102) after 6 months of treatment at VDZ, and the recurrence rate of fistula in patients with inactive fistula was 30.
6% (15/49)
during the average follow-up period of 39 weeks after treatment.

In a recent randomized, double-blind controlled study comparing conventional and escalated doses of VDZ (one additional dose at week 10) for fistula [20], 79 percent of patients had received anti-TNF therapy, showed an overall healing rate of 42.
9 percent (12/28) of fistula at 30 weeks, with no statistically significant
difference in fistula healing between groups.
The study concluded that VDZ was similar to anti-TNF preparations for dystrophy, but there was no placebo control in the study and 92% of patients had fistula hangings at baseline, which affected the confidence of the study
conclusions.

Overall, for CD fistula, moderate evidence supports IFX induction and maintenance of remission, low evidence supports UST induction and maintenance of remission, and low evidence supports ADA maintenance of remission, and further studies are needed to support ADA and VDZ-induced remission [10].

(2) Extraintestinal manifestations of IBD: Except for a randomized double-blind placebo-controlled study of IFX in the treatment of pyoderma gangrenosum [21], the current evidence on the efficacy of biologics in the treatment of extraintestinal manifestations (EIM) in IBD comes from RCT post-hoc analysis or observational studies
in the treatment of IBD.
Anti-TNF has been systematically reviewed in the literature

Efficacy
of formulations [22], UST [23], and VDZ [24] in the treatment of extraintestinal manifestations.
A recently published literature on the evaluation and use of biologics for parenteral manifestations serves as an important reference [25].

Treatment of extraintestinal manifestations associated with intestinal inflammatory activity in IBD focuses on controlling intestinal IBD inflammatory activity
.
Biologics that may have a targeted effect on extraintestinal manifestations include: (1) Anti-TNF agents: effective
for extraintestinal manifestations of the skin, joints and eyes.
It should be emphasized that there is sufficient evidence for the efficacy of anti-TNF agents in the treatment of axial arthritis and pyoderma gangrenosum, and their efficacy in concomitant rheumatoid arthritis and ankylosing spondylitis has long been recognized
by rheumatology.
(2) UST: effective for peripheral arthritis or peripheral joint pain, especially suitable for psoriatic arthritis, but not for axial arthritis; may be effective for cutaneous extraintestinal manifestations (erythema nodosum and pyoderma gangrenosum); The efficacy of uveitis has yet to be further demonstrated
.
(3) VDZ: There is currently insufficient evidence to support its targeted efficacy
on extraintestinal manifestations.
With VDZ controlling intestinal inflammatory activity, extraintestinal manifestations closely related to intestinal inflammatory activity in IBD may be improved as a result, and have been reported to be effective for peripheral arthritis or peripheral arthralgia, but further studies
are needed.

(2) Moderate to severe UC

At present, there is only one head-to-head RCT study (VARSITY study) comparing the efficacy of biologics in the treatment of moderate to severe UC, and the results show that the clinical response rate and mucosal healing rate of VDZ treatment at 52 weeks are significantly higher than those of ADA (31.
3% vs.
22.
5%, 95%CI: 2.
5~15.
0, P = 0.
006; 39.
7% vs.
27.
7%, 95%CI:5.
3~).
18.
5, P<0.
001), and there was no significant difference between the clinical response rates without hormones; further subgroup analysis found that there was no significant difference in efficacy between the two groups only UC patients who had not received anti-TNF preparations [26].
<b10>

In terms of comparing the efficacy of various biologics in the treatment of UC, a recently published online meta-analysis literature is representative [27].

Fifteen RCTs (3747 patients) treated with first-line biologics were included in the literature, and the results showed that the surface under the cumulative ranking curve (SUCRA) for clinical response rate and mucosal healing rate were IFX 0.
95 and 0.
95, VDZ 0.
76 and 0.
63, tofacitinib 0.
56 and 0.
47, UST 0.
49 and 0.
44, ADA 0.
32 and 0.
35, with IFX at the top
.
Moderate evidence supports better clinical response rates than ADA in IFX-induced UC, but there is no statistically significant
difference in efficacy between other biologics.
Seven RCTs (1580 patients) treated with second-line biologics were also included, and the SUCRAs for clinical response and mucosal healing rates were: tofacitinib 0.
91 and 0.
87, UST 0.
83 and 0.
87, VDZ 0.
34 and 0.
48, and ADA 0.
26 and 0.
15, with tofacitinib and UST ranked high
.
Moderate evidence supports the superiority of tofacitinib and UST-induced UC clinical remission over ADA and VDZ
.
There was a statistically significant
difference in efficacy in maintaining clinical remission between various biologics.

Many real-world studies of VDZ in the treatment of moderate to severe UC have been reported
.
In a retrospective analysis of 376 patients with UC treated with VDZ and 221 patients treated with anti-TNF agents, there was no significant difference in clinical response rate and mucosal healing rate between the two biologics at 24 weeks (65.
9% versus 48.
6%, P = 0.
09; 86.
6% versus 80.
6%, P = 0.
66) [12]
。 Another recently published multicenter retrospective study of 454 UC patients treated with VDZ and 268 treated with anti-TNF agents showed that the rate of hormone-free deep response was significantly higher in VDZ than with anti-TNF preparations (HR = 2.
819, 95% CI: 1.
496 ~ 5.
310); The incidence of serious adverse reactions of VDZ as a first-line biologic agent was significantly lower than that of anti-TNF preparations (HR = 0.
192, 95% CI: 0.
049 ~ 0.
754) [28]
.
In a national registry study in Australia reporting long-term maintenance therapy with various biologics, the proportion of long-term maintenance therapy in VDZ was significantly higher than that of anti-TNF agents in patients with moderate to severe UC (HR = 1.
67, 95% CI: 1.
27 ~ 2.
18, P<0.
001), and long-term maintenance therapy was associated with previous use of biologic agents [29]<b13>.
The results of another efficacy prediction model showed that VDZ efficacy correlated with previous biologic use and endoscopic severity at initiation [30].

In general, from the perspective of efficacy, according to the current clinical evidence, IFX and VDZ are recommended as first-line biologics for the treatment of moderate to severe UC, and acute severe UC should be treated with IFX, and the efficacy of VDZ and IFX is better than that of ADA, but ADA is convenient to administer and can still be used as an alternative drug for patients with mild disease [8⁃9].

For primary or secondary failure of anti-TNF preparations, AGA and ECCO recommend UST or tofacitinib treatment, which is better than ADA or VDZ [8⁃9], but at present, these two drugs are not approved as UC indication drugs
in China.
VDZ therapy is an option in this setting, especially in patients with mild UC [30].

IFX can be switched to those who do not respond to VDZ, but there is insufficient evidence
.
In general, remission-inducing drugs are used to maintain UC remission
.

Third, the safety comparison of various biological agents

The evidence for the safety of various biologics is mainly derived from RCTs, observational studies, and post-marketing registry studies, and there have been many relevant systematic analyses [31] and reviews [32].

(1) Opportunistic infections and serious infections

1.
Anti-TNF agents: Anti-TNF preparations increase the risk of opportunistic infections and serious infections, especially may activate latent tuberculosis infection, increase new tuberculosis infection and activate hepatitis B virus infection
.
In a meta-analysis of 22 RCTs, opportunistic infection rates were higher in the anti-TNF group than in the placebo group (0.
9% versus 0.
3%, RR = 2.
05, 95% CI: 1.
10 ~ 3.
85), with significantly higher rates of TB infection (RR = 2.
52, 95% CI: 0.
62 ~ 10.
21) [33]
。 In a 13-year registry study (TREAT study) in the United States, the rate of serious infection with CD treated with IFX was significantly higher than in the nonbiologic group (2.
15 versus 0.
86 per 100 person-years) [34]
。 A national cohort study in France included 190 694 patients with IBD, divided into groups that did not receive mercaptopurines and anti-TNF preparations, mercaptopurine groups, anti-TNF single-agent groups, and anti-TNF preparations and mercaptopurine combination treatment groups, respectively, with serious infection rates of 8.
4, 10.
5, 18.
9, and 22.
4/1000 person-years, respectively, of which the anti-TNF single-agent group was higher than the mercaptopurine group (HR =1.
71), The combination treatment group was higher than the anti-TNF monotherapy group (HR = 1.
23); Opportunistic infection rates were 0.
4, 1.
7, 2.
1, and 4.
1 per 1000 person-years, respectively, and although the overall opportunistic infection rate was not significantly higher in the anti-TNF monotherapy group than in the mercaptopurine group, tuberculosis infection was significantly increased (HR = 1.
98), and the opportunistic infection rate in the combination therapy group was higher than that in the anti-TNF monotherapy group (HR =1.
96) [35]
.
Disease activity, duration, steroid combination, and older patients are risk factors for opportunistic and severe infections with anti-TNF preparations for IBD [31].

2.
VDZ: In a meta-analysis of 6 clinical studies with a total of 2830 patients with IBD followed for 5 years, the rate of serious infection in VDZ was similar to placebo (4.
3 versus 3.
8 per 100 person-years), no patients had hepatitis B virus activation, and the incidence rates of Clostridium difficile infection and Mycobacterium tuberculosis infection were low in the VDZ treatment group, 0.
4 and 0.
1 per 100 person-years, respectively, but no infection in the placebo group [36].

。 A statistical study based on the databases of 2 US and 1 French insurance companies included a total of 8768 patients with IBD in the VDZ group and 26 656 patients with IBD in the anti-TNF group, and there was no significant difference in the overall serious infection rate between the two groups (HR = 0.
95, 95% CI: 0.
79 ~ 1.
13), but VDZ treated UC

The rate of serious infection was lower than that of anti-TNF agents (HR = 0.
68, 95% CI: 0.
50 ~ 0.
93), while there was no significant difference in patients with CD [37].

3.
UST: UST was first used for the treatment
of psoriasis.
In the PSOLAR registry study of 12,093 patients with psoriasis in the United States, the serious infection rates in the UST, IFX and other biologics groups were 0.
93, 2.
91, and 1.
91/100 person-years, respectively, and the severe infection rates of IFX were significantly higher than those in the UST group after combination with other biologics (HR = 1.
96, P<0.
001) [38]<b11>.
In a study from South Korea, where tuberculosis is high-endemigine, the incidence of tuberculosis in the treatment of psoriasis by UST was not significantly different from that of the general population [39].

However, UST treats psoriasis at half the dose of IBD, so its safety in the treatment of IBD still needs to be confirmed
by more and longer-term studies.
In the recently published IM⁃UNITI study of UST for the treatment of CD, there was no significant difference in the rate of serious infection compared with placebo (3.
9 versus 3.
4 per 100 person-years) at five years of follow-up after UST treatment, and only one patient developed active tuberculosis [40].

A systematic review of observational studies suggested that the rate of serious infection with UST treatment was 5.
6 percent, and no tuberculosis infection was reported [41].

Overall, patients treated with UST have a lower probability of opportunistic and serious infections, including latent TB activation or new-onset TB, compared with anti-TNF agents, but further studies are needed to confirm their clinical use due to their
short clinical use.
VDZ is intestinally specific, theoretically does not increase the risk of opportunistic infections of other systems and systems, and clinical evidence also shows that the risk of infection is lower than that of anti-TNF agents, which may be the biological agent with the lowest risk of infection at present, but the risk of intestinal infections, especially Clostridium difficile infection, needs to be further studied
.

(2) Malignant tumors

1.
Anti-TNF agents: Previous studies have linked the risk of lymphoma to combination with mercaptopurines, and it is unclear whether anti-TNF agents increase the risk of lymphoma [42].

。 A recent French national cohort study published in JAMA followed 189 289 patients with IBD, with an average follow-up time of 6.
7 years, and found that those with mercaptopurines alone and anti-TNF preparations alone had an increased risk of lymphoma compared with those who did not use these two drugs, and that patients with IBD who combined anti-TNF preparations and mercaptopurines had a higher risk of lymphoma than those with mercaptopurines alone (adjusted HR = 2.
35, 95% CI: 1.
31~).
4.
22, P<0.
001) and anti-TNF preparation alone (corrected HR = 2.
53, 95% CI: 1.
35 ~ 4.
77, P<0.
001) [43]<b11>.
Anti-TNF agents may not increase the risk of nonmelanoma skin cancer, but may increase the risk of melanoma, a conclusion that has not been confirmed in studies of rheumatic diseases [31⁃32].

2.
UST and VDZ: In PSOLAR studies for the treatment of psoriasis, UST was not observed to increase the risk of malignant neoplasms [38].

At present, UST and VDZ have not been found to increase the risk of malignant tumors in IBD studies, but due to the short clinical application time, further research
is needed.

(3) Impact on pregnancy

The risk level of use of IFX, ADA, VDZ, and UST during pregnancy is rated B (low risk)
by the U.
S.
Food and Drug Administration (FDA).
A recent review of 48 studies of 6963 pregnant women with IBD who used biologics showed no statistically significant difference in pregnancy outcomes from those used in pregnancy compared with the general population [44]
.
Since it has been established that IBD itself has a significant impact on pregnancy outcomes, and discontinuation of biologics is prone to disease recurrence, continued use of biologics throughout pregnancy is recommended if required [44⁃45].

Although the increased rate of placental passage with IFX in the third trimester of pregnancy theoretically may affect neonatal immune function, this effect was not observed in clinical systematic reviews [44].

The Toronto Consensus recommends the use of biologics throughout pregnancy and can be temporarily discontinued in the third trimester if special considerations are given and the disease is well controlled [46].

Data are limited and it is not possible to compare differences in the effects of various biologics on pregnancy outcomes [44⁃45].

(4) Drug immunogenicity

The secondary failure of anti-TNF preparations is related to their immunogenicity (production of antidrug antibodies), and the combination of immunosuppressants (mercaptopurines or methotrexate) can reduce their immunogenicity
.
IFX plus azathioprine for IBD has been outperformed by RCTs [5,8].

Another RCT suggested that when one anti-TNF agent is converted to another anti-TNF agent due to secondary failure, azathioprine is significantly more effective than that of biologic alone [47].

However, combination increases the risk of
adverse effects.
UST and VDZ are low
immunogenicity.
A systematic review showed that the production rates of antimicrobodies of IFX, ADA, UST and VDZ were 0 ~ 65.
1%, 0.
3% ~ 38.
0% and 1.
0% ~, respectively

4.
1% and 0.
7% [48] .

Current research evidence does not show additional efficacy benefit from UST and VDZ in combination with immunosuppressants [5,8].

The immunogenicity of anti-TNF agents also increases the risk of immune diseases such as drug-induced lupus erythematosus, dermatomyositis, and psoriasis, but UST and VDZ have not been reported [32].

IV.
Recommendations on the selection and conversion of biologics in clinical practice

The choice of drug needs to weigh the benefit and risk ratio, taking into account both the severity of the patient's disease and the need
for safety due to physical condition.
Based on the above comparative analysis of the efficacy and safety of various biological agents, combined with international mainstream opinions and China's application experience, the selection and conversion of currently approved biologics for the treatment of CD and UC are proposed (Figures 1 and 2).

Of course, when using it, the doctor needs to take into account the local conditions and the patient's wishes
.
When IBD is associated with other clinical conditions such as fistula and extraintestinal manifestations, the choice of biologic agent can be seen above
.

V.
Prospects

The new biologics will help improve the efficacy of IBD, especially refractory IBD, but at the same time increase clinician confusion
about drug selection and conversion.
Current research evidence is insufficient to accurately evaluate the efficacy and safety of various biologics, and in most cases clinicians make empirical drug selection and switching
.
More research is needed, especially head-to-head RCTs, to further compare the efficacy and safety of various biologics, and to establish efficacy prediction models to guide individualized medication
.
With more and more biologics and low molecular weight drugs on the market, how to efficiently solve these problems is very urgent
.