Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic inflammatory disorder of the intestine. The incidence of IBD continually increases worldwide, inducing a tremendous economic burden on patients and society (Kaplan, 2015). Although the disease’s pathogenesis is unclear, it may correlate to genetic susceptibility, environmental factors, and gut dysbiosis. All the disorders above lead to immune imbalance and consequently to the development of diseases, which are usually mediated by Th1 and Th17 cells. They produce large amounts of cytokines such as TNF-α, IL-17, and IL-1β (Romagnani, 1999; Torres et al., 2017), which cause chronic inflammatory response increasing. As the research progresses, traditional treatments (including 5-aminosalicylic acid, glucocorticoids, immunosuppressants, etc.,) have shifted to biological therapy (Pouillon et al., 2020). There has been an increasing number of biologic medications used for IBD treatment, such as monoclonal antibodies or inhibitors to tumor necrosis factor (TNF)-α, interleukin (IL)-12/23, adhesion molecules, and Janus kinase (JAK). Biologics open up a new era of IBD treatment.

During the last 40 years, the cellular and molecular mechanisms of the inflammatory diseases’ pathogenesis have been continuously revealed, including UC, CD, ankylosing spondylitis (AS), rheumatoid arthritis (RA), and psoriasis. Among all inflammatory cytokines and chemokines, TNF-α is the first identified vital factor in developing the inflammatory responding process. Thus anti-TNFα therapy emerged and began to use in RA treatment in the mid-1990 s, and therapeutic goals started to evolve and move forward. Due to its potential effect on disease-modifying and mucosal healing, anti-TNFα therapy is associated with a reduced risk of hospitalization, colectomy, and colorectal cancer, especially among IBD patients. Anti-TNFα acts mainly by binding TNF-α in serum (sTNFα) or on immune cell membranes (mTNFα) (Tracey et al., 2008), and especially the latter is considered as a critical role in biological agents function. Anti-TNFα is the most classic of all biologics, including infliximab (IFX) and adalimumab (ADA). Because of the safety and convenient usage, human-originated and subcutaneous injecting ADA and its biosimilars have been widely used (Sandborn et al., 2007). European Crohn’s and Colitis Organization (ECCO) and the American College of Gastroenterology (ACG) have made it clear that ADA can be used as an option for patients with moderate-severe IBD who do not respond to conventional therapy or are intolerant (Rubin et al., 2019; Raine et al., 2022). Biosimilars are biological agents with similar therapeutic effects to approved reference drugs regarding quality, efficacy, and safety. Biosimilars have great potential for cost savings and extraordinary accessibility (Kim et al., 2020). The first biosimilar for IFX (CT-P13) was available in 2013, whereas ADA biosimilars have been licensed since 2017. ADA biosimilar HS016 used in this study has completed a phase III clinical trial in patients with ankylosing spondylitis (AS) (Su et al., 2020). The results showed similar efficacy and safety compared with the ADA originator (Humira). Then it was validated by antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity (Gao et al., 2022).

Consequently, HS016 became China’s first ADA biosimilar approved for CD indications. Several randomized clinical trials, including CLASSIC-I, CHARM, ULTRA 1, and ULTRA 2 (Hanauer et al., 2006; Colombel et al., 2007; Reinisch et al., 2011; Sandborn et al., 2012), demonstrated the efficacy and safety of ADA in moderate to severe CD and UC treatment. Multiple real-world data have also confirmed the effectiveness of ADA in CD and UC therapy (Sohn et al., 2016; Moens et al., 2022; Vitello et al., 2022). ECCO and AGA guidelines also propose that the safety and efficacy of the original ADA and biosimilars are consistent. Still, the biosimilar of ADA in China (HS016) is different from the ADA originator or the biosimilars in Europe and the United States (SB5, BI95501) (Derikx et al., 2021; Hanauer et al., 2021).

Although anti-TNFα unveils a new treatment for IBD, up to 30% of patients show primary nonresponse (PNR), and another 40% lose response over time, i.e., secondary loss of response (SLR) and need to switch therapy (Papamichael et al., 2015). So far, these patients obtained no benefit, are caused by inadequate drug concentrations or an increased drug clearance (Papamichael and Cheifetz, 2017). Therapeutic drug monitoring (TDM) has already become a practical tool for the therapeutic management and optimization of anti-TNFα agents, including measuring serum and anti-drug antibody concentrations. Thus, serum drug concentrations have already been used as one of the biologics efficacy indicators. Higher serum drug concentrations are usually considered an objective outcome of treatment, while the lower suggest shortening dosing intervals or switching the treatment method. In comparison, anti-drug antibodies are a factor in lower drug concentration, so it is necessary to add immune suppressants or convert therapy (Papamichael et al., 2015; Vaughn et al., 2015).

In this study, we retrospectively analyzed the real-world data of HS016 in IBD treatment from one of the biggest IBD centers in China. In addition, we further discussed the factor (TDM) on the efficacy of HS016, providing more evidence and suggestions for clinical decision-making.

The primary outcomes of this study show that HS016 has a significant therapeutic effect on IBD patients, and the most frequent factor for the ineffective HS016 treatment is insufficient serum concentration. Our research proves to physicians that HS016 is a practical and safe treatment option for IBD.

Compared to IFX, ADA is a fully human-originated antibody with lower immunogenicity and higher safety. The subcutaneous injection mode of administration makes its application more and more widespread. A large number of studies have demonstrated the efficacy of ADA for IBD. For example, CLASSIC- I (Hanauer et al., 2006) reported a clinical remission rate of 36% at 4 weeks with ADA in CD patients, which was significantly better than the placebo-controlled group. CLASSIC- II (Sandborn et al., 2007) showed induction remission of CD was 46% at 56 weeks. In addition, several domestic and international studies (Derikx et al., 2021; Hanauer et al., 2021; Tursi et al., 2022) affirmed the efficacy of other ADA biosimilars (SB5, BI95501), including IBD patients initially treated with ADA biosimilar and in conversion from the original ADA. EXTEND (Rutgeerts et al., 2012) indicated that the mucosal healing rates among ADA-treated CD patients were 27% at 12 w and 24% at 52 w, respectively. However, there are no relevant data on the efficacy of HS016 in China, and our study confirmed its effectiveness and safety. Our results were similar to or better than the present studies.

On the one hand, the efficacy of HS016 is confirmed. On the other hand, 98% of CD patients in our study were mild to moderate. It also shows that early application of biologics can improve the cure rates of IBD patients. All findings above suggested that ADA biosimilar HS016 showed similar efficacy as the original ADA.

Moens et al. (Moens et al., 2022) also revealed that ADA for UC had a clinical remission rate of 26% at 26 weeks. At the same time, the results of Iborra M et al. (Iborra et al., 2017) showed clinical remission rates of 26% and 43% at 12 and 26 weeks, respectively. Although ADA is not often used to treat UC in China (due to China’s FDA policies), ECCO, ACG (Rubin et al., 2019; Raine et al., 2022) have clarified that ADA can be used for the treatment of moderately severe UC in adults, especially those with inadequate, intolerant, or contraindicated response to glucocorticoid therapies. Compared to the studies above, our study’s lower clinical remission rates (31.3% at 26 w) may be mainly due to the sample size and a high proportion of patients with severe inflammation (56.9%) at baseline. Therefore, further investigation with more data is still needed.

Regarding safety, PYRAMID (DʼHaens et al., 2018) with up to 6 years of follow-up, confirmed the safety of ADA, which did not increase the risk of various side effects, such as lymphoma. A meta-analysis (Singh et al., 2011) included 160 randomized controlled studies and pointed out no additional risk of overall or severe adverse events, serious infections, or withdrawal study due to adverse events compared to the placebo. The incidence of ADA biosimilar adverse events, reported in the VOLTAIRE-CD (Hanauer et al., 2021), showed that the most common occurring infection (24%) and injection reaction (23%) rates were similar to ADA originator. The occurrence of side effects in IBD patients treated with HS016 was 5.5% (5/91), including psoriatic-like rash and fungal otitis externa, which had also been reported with the original ADA. Moreover, Cao et al. discovered that an allergic reaction, which appeared in a patient because of the original drug, would recover after conversion to ADA biosimilar (Cao et al., 2022). Although it is a case report, it may still demonstrate biosimilars is safer than original drug in certain aspects.

Anti-TNFα biologics mainly treat IBD by inactivating inflammatory factors, thus inhibiting inflammation (Tracey et al., 2008; Allez, 2012). Our study analyzed the correlation between serum TNF-α levels and disease severity (SES-CD/CRP) in 20 CD patients treated with HS016 for ≥ 3 months. The results showed no significant correlation between serum TNF-α levels and the severity of the disease. However, all 20 patients’ serum TNF-α levels remained elevated after therapy; some were in clinical remission. Additionally, a previous study (Martínez-Borra et al., 2002) concluded that the serum levels of TNF-α are associated with the response to infliximab and could help to identify patients who would benefit from anti–TNFα treatment. But more studies (Louis et al., 2002; Amini Kadijani et al., 2017; Billiet et al., 2017) showed the opposite. In our study, most patients tested for serum TNF-α concentrations, were subject to persistent endoscopic nonresponse after HS016 application, which may impact the analysis of the results. And only one time point of serum TNF levels is available for this analysis. Thus, the significance of serum TNF-α in IBD diagnosis and treatment remains unclear, and further research is needed to investigate the changes in TNF levels before and after TNF treatment.

Although a wide range of studies have demonstrated that TNF-α inhibitors are effective therapies for IBD, there are still approximately 40% of patients will experience primary nonresponse (PNR) or secondary loss of response (SLR) (Argollo et al., 2020). In our data, PNR is 12.0%, and SLR is 22.7%, which is highly consistent with the previous findings. Then dose increasing or treatment switching can both be executed based on TDM. We further analyzed the reasons for failing to respond. On the one hand, only one (4.3%) patient showed no response, possibly due to the production of anti-antibodies, which is lower than reported data in others (Kennedy et al., 2019).

On the other hand, 7 (30.4%) patients may have had inadequate drug concentrations (the drug concentration < 5 μg/mL), resulting in loss of response. However, different studies have inconsistent recommendations for the recommended concentration of ADA. One study suggests that ADA concentration >4.9 μg/mL is beneficial for mucosal healing in CD patients (Roblin et al., 2014). Another study suggests that ADA concentration should be >7.1 μg/mL for mucosal healing (Ungar et al., 2016). In conclusion, regardless of the classification, TDM can only indicate that the inadequate drug concentration may be a possible reason for the poor treatment response in some patients. There are still some limitations when applying TDM within clinical practice, such as when to use TDM and how to interpret and apply the results correctly. Currently, reactive TDM is regarded as the standard of care, while proactive TDM is developed as a new therapeutic strategy to optimize anti-TNFα therapy in IBD. More data are still needed to define optimal drug concentration by well-designed prospective studies and RCT focusing on proactive TDM, especially during induction therapy (Papamichael et al., 2019; Papamichael et al., 2022).

In conclusion, we have confirmed the efficacy and safety of ADA biosimilar HS016 among Chinese IBD patients. In particular, the real-world data is equal to the previously reported RCT studies on the effectiveness of HS016 with Chinese CD patients. As research continues, we are confident that increasing biological agents will appear for IBD therapy. Additionally, biosimilars will stimulate competition in the market and have incredible potential to expand patient exposure to biologics in the context of treatment recommendations. Appropriate use of TDM will provide physicians with a more significant basis for selecting and optimizing treatment.

Herein, we demonstrate that HS016 may be an effective and safe option for Chinese IBD patients.