Infliximab is considered the first-line drug for moderate and severe CD [4, 6]. However, many patients still experience a loss of response during treatment [4, 5]. The ability to screen CD patients who can obtain better curative effects and then implement individualized treatment for patients can maximize the drug's efficacy, reduce drug toxicity, and avoid unnecessary economic expenses.
The results of our study showed that sarcopenia is a risk factor for LOR in CD patients treated with infliximab. Currently, the standard treatment of infliximab is body weight-based intravenous administration. However, the concentration-time profile of infliximab in CD patients is highly variable between individuals, with body weight being considered as one possible cause[21]. Fasanmade et al. [22] suggested that other parameters such as lean body mass may be more precise than body weight. Furthermore, Iris et al. [23] found that the relationship between the clearance rate of infliximab and body weight is non-linear, but there is a linear relationship between dose and body weight. So, if the drug is administered according to 5 mg/kg criteria, patients with lower body weight have approximately 35% less drug exposure than patients with twice their body weight. Therefore, low-weight patients may have lower trough levels of infliximab and high-weight patients may benefit more from this weight-based dosing pattern. And, our study found sarcopenia CD patients have lower BMI than non-sarcopenic CD patients, so we thought that the relative acceleration of drug clearance rate might be one of the reasons for the LOR to infliximab therapy in sarcopenia CD patients.
In addition, study found that the sarcopenia group had higher surgery, re-hospitalization and death rate than the control group in patients with inflammatory bowel disease [24]. And, intensifying the dose of infliximab with LOR on standard dosing patterns can improve the mucosal healing rate[25]. So, we thought that sarcopenia may reflect the severer inflammatory state of the patient, which requires higher doses of infliximab support than the standard dose. And this might be another reason for the LOR of infliximab therapy in sarcopenia CD patients. Furthermore, Subramaniam et al. [26] demonstrated that infliximab therapy could increase muscle volume and muscle strength in CD patients to reverse sarcopenia, while Zhou et al. suggested that the increase in SMI could reflect improved inflammatory status[27]. These studies demonstrate a reciprocal relationship between infliximab therapy and sarcopenia.
This study found that females had a lower risk of sarcopenia than males (OR = 0.30, 95%CI 0.11–0.81, P = 0.017). A Japanese study[28] showed that the skeletal muscle content of men's upper and lower limbs is about 40% and 30% higher than that of women respectively. Besides, another study[29] found that the relative and absolute amounts of muscle loss in males are higher than in females with aging, suggesting that males are more prone to muscle loss than females. In addition, although the specific mechanism of the effect of estrogen on muscle metabolism is not clear yet, studies have shown that estrogen may have anti-inflammatory and anti-catabolic effects on skeletal muscle [30]. We believe these may be the reasons for the higher risk of sarcopenia in male CD patients. Our results showed that BMI was significantly associated with sarcopenia (OR = 0.68, 95%CI 0.56–0.83, P < 0.001), suggesting that patients with low BMI are more likely to have sarcopenia. Nevertheless, this study showed a poor correlation between BMI and the LOR of infliximab. A possible reason could be that patients with high BMI were more likely to gain fat mass rather than muscle mass[20].
This study also showed that L1 CD and L2 CD had a lower risk of sarcopenia than L3 CD (OR = 0.29, 95%CI 0.10–0.83, P = 0.021; OR = 0.25, 95%CI 0.07–0.87, P = 0.028). A Danish study [31] demonstrated that 16 (28%) L1 patients and 12 (14%) L2 patients converted to L3 during a 7-year follow-up, and patients who progressed in changed locations had an increased risk of surgery. L3 CD patients are also considered to have a higher risk for phenotypic progression[32]. We thought that patients with L3 type might lead to more serious nutrient consumption and malabsorption due to the wider range of lesions than L1 and L2 types.
It is generally considered that VFA ≥ 130 cm2 is a simple and feasible criterion for defining visceral adiposity [33]. According to this standard, only 3(2.5%) patients with visceral adiposity were observed in our study cohort. But studies showed that CD patients have increased visceral fat area over time and are higher than normal controls [34, 35]. The possible reasons for this difference may be as follows: in this study, we measured the body composition of patients who did not receive standard treatment. Their median BMI was 18.66 (16.79, 20.87), which is indicative of poor nutritional status. Additionally, our results showed that subcutaneous fat area, visceral fat area, and mesenteric fat index were poorly correlated with LOR while Lim et al. [20] found that visceral adiposity was associated with IFX trough levels and could predict secondary loss of response to adalimumab treatment in CD patients. Furthermore, Ding et al [36] and Li et al [18] showed that the visceral fat area was less associated with LOR, drawing similar conclusions to this study. Li et al [18] also found that lower mesenteric fat index is a risk factor for LOR to infliximab therapy, while Shen et al. [37] suggested that high mesenteric fat index and visceral fat area are risk factors for poor mucosal healing in CD patients after infliximab therapy. In conclusion, there is currently no consensus on the relationship between fat-related body composition parameters and the efficacy of infliximab.
This study has a few limitations. Firstly, due to the retrospective nature of the study, selection bias may have been introduced. Also, CT examination was more likely to be performed in patients with severer inflammatory status, and we failed to combine the muscle strength (handgrip strength, etc.) and physical performance (6-minute walk test, etc.) into sarcopenia studies. Secondly, in this study, the cut-off value proposed by Carla et al. [19] was used to diagnose sarcopenia, and the optimal cut-off value is still controversial. Finally, we did not use primary nonresponse and secondary loss of response to assess the efficacy of infliximab therapy cause the adjustment of the treatment plan always lags with the change in the patient's condition in clinical practice, so it was hard to distinguish patients with primary nonresponse or secondary loss of response.